Redox carriers for brain-specific drug delivery

ABSTRACT

Compounds of the formula ##STR1## and the nontoxic pharmaceutically acceptable salt thereof, wherein D is the residue of a centrally acting drug containing at least one reactive functional group selected from the group consisting of amino, hydroxyl, mercapto, carboxyl, amide and imide, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups in said drug; n is a positive integer equal to the number of said functional groups from which a hydrogen atom is absent; and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine⃡pyridinium salt redox carrier, said carrier comprising a bivalent radical of the formula ##STR2## wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R o  is a radical identical to the corresponding portion of a natural amino acid; and p is 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R o  radicals can be the same or different; said bivalent radical being so positioned that the terminal carbonyl function of the bivalent radical is linked to the drug residue while the terminal amino function of the bivalent radical is linked to the remaining portion of the carrier moiety; are adapted for the site-specific/sustained delivery of centrally acting drugs to the brain. The corresponding pyridinium salt type drug/carrier entities D --QC +  ] n  qY -t  are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 07/295,663, filedJan. 11, 1989, now U.S. Pat. No. 5,087,618, which is a division ofapplication Ser. No. 06/666,210, filed Oct. 29, 1984, now U.S. Pat. No.4,829,070, which is a continuation-in-part of my earlier applicationsSer. No. 06/379,316, filed May 18, 1982, now U.S. Pat. No. 4,479,932;Ser. No. 06/461,543, filed Jan. 27, 1983, abandoned in favor of Ser. No.06/733,463, filed May 13, 1985, now U.S. Pat. No. 4,727,079; Ser. No.06/475,493, filed Mar. 15, 1983, now U.S. Pat. No. 4,622,218; and Ser.No. 06/516,382, filed Jul. 22, 1983, now U.S. Pat. No. 4,540,564. Eachof said earlier copending applications is hereby expressly incorporatedby reference in its entirety and relied upon.

FIELD OF THE INVENTION

The present invention relates to a dihydropyridine/pyridinium salt typeof redox system for the site-specific or sustained delivery (or both) ofa wide variety of drug species to the brain. More especially, thisinvention relates to the discovery that a biologically active compoundcoupled to a lipoidal carrier moiety comprising a dihydropyridinenucleus readily and easily penetrates the blood-brain barrier ("BBB")and attains increased levels of concentration in the brain; oxidation ofthe dihydropyridine carrier moiety in vivo to the ionic pyridinium saltprevents its elimination from the brain, while elimination from thegeneral circulation is accelerated, resulting in significant andprolongedly sustained brain-specific drug activity, whether ascribableto the cleavage of the drug/quaternary entity and sustained release ofthe drug in the brain and/or to the drug/quaternary itself.

BACKGROUND OF THE INVENTION

The delivery of drug species to the brain is ofttimes seriously limitedby transport and metabolism factors and, more specifically, by thefunctional barrier of the endothelial brain capillary wall deemed theblood-brain barrier, BBB. Site-specific delivery and sustained deliveryof drugs to the brain are even more difficult.

It has been previously suggested to deliver a drug species, specificallyN-methylpyridinium-2-carbaldoxime chloride (2-PAM), into the brain, theactive nucleus of which in and of itself constitutes a quaternarypyridinium salt, by way of the dihydropyridine latentiated prodrug formthereof. Such approach was conspicuously delimited to relatively smallmolecule quaternary pyridinium ring-containing drug species and did notprovide the overall ideal result of brain-specific, sustained release ofthe desired drug, with concomitant rapid elimination from the generalcirculation, enhanced drug efficacy and decreased toxicity. Hence, no"trapping" in the brain of the 2-PAM formed in situ resulted, andobviously no brain-specific, sustained delivery occurred as anyconsequence thereof: the 2-PAM was eliminated as fast from the brain asit was from the general circulation and other organs. Compare U.S. Pat.Nos. 3,929, 813 and 3,962,447; Bodor et al, J. Pharm. Sci., 67, No. 5,pp. 685-687 (1978); Bodor et al, Science, Vol. 190 (1975), pp. 155-156;Shek, Higuchi and Bodor, J. Med. Chem., Vol. 19 (1976), pp. 113-117. Amore recent extension of this approach is described by Brewster,Dissertation Abstracts International, Vol. 43, No. 09, March 1983, p.2910B. It has a also been speculated to deliver, e.g., an antitumoragent, into the brain by utilizing a dihydropyridine/pyridinium redoxcarrier moiety therefor, but this particular hypothesis necessarilyentails derivatizing the dihydropyridine/pyridinium carrier with asubstituent itself critically designed to control the release rate ofthe active drug species itself; Bodor et al, J. Pharm. Sci., supra. Seealso Bodor, "Novel Approaches for the Design of Membrane TransportProperties of Drugs", in Design of Biopharmaceutical Properties ThroughProdrugs and Analogs, Roche, E. B. (ed.), APhA Academy of PharmaceuticalSciences, Washington, D.C., pp. 98-135 (1976).

More recently, the present inventor and his coworkers, in Bodor et al,Science, Vol. 214, December 18, 1981, pp. 1370-1372, have reported onsite-specific sustained release of drugs to the brain. The Sciencepublication outlines a scheme for specific and sustained delivery ofdrug species to the brain, as depicted in the following Scheme: ##STR3##According to the scheme in Science, a drug [D] is coupled to aquaternary carrier [QC]⁺ and the [D-QC]⁺ which results is then reducedchemically to the lipoidal dihydro form [D-DHC]. After administration of[D-DHC] in vivo, it is rapidly distributed throughout the body,including the brain. The dihydro form [D-DHC] is then in situ oxidized(rate constant, k₁) (by the NAD⃡NADH system) to the ideally inactiveoriginal [D-QC]⁺ quaternary salt which, because of its ionic,hydrophilic character, should be rapidly eliminated from the generalcirculation of the body, while the blood-brain barrier should preventits elimination from the brain (k₃ >>k₂ ; k₃ >>k₇). Enzymatic cleavageof the [D-QC]⁺ that is "locked" in the brain effects a sustaineddelivery of the drug species ]D], followed by its normal elimination(k₅), metabolism. A properly selected carrier [QC]⁺ will also be rapidlyeliminated from the brain (k.sub. 6 >>K₂). Because of the facileelimination of [D-QC]⁺ from the general circulation, only minor amountsof drug are released in the body (k₃ >>k₄); [D] will be releasedprimarily in the brain (k₄ >k₂). The overall result ideally will be abrain-specific sustained release of the target drug species.

Bodor et al have reported, in Science, their work with phenylethylamineas the drug model, which was coupled to nicotinic acid, then quaternizedto give compounds of the formula ##STR4## which were subsequentlyreduced by sodium dithionite to the corresponding compounds of theformula ##STR5## Testing of the N-methyl derivative in vivo supportedthe criteria set forth in the Scheme. Bodor et al speculated thatvarious types of drugs might possibly be delivered using the depicted oranalogous carrier systems and indicated that use of N-methylnicotinicacid esters and amides and their pyridine ring-substituted derivativeswas being studied for delivery of amino- or hydroxyl-containing drugs,including small peptides, to the brain. No other possible specificcarriers were disclosed.

Other reports of the present inventor's work have appeared in The FridayEvening Post, Aug. 14, 1981, Health Center Communications, University ofFlorida, Gainesville, Fla.; Chemical & Engineering News, Dec. 21, 1981,pp. 24-25; and Science News, Jan. 2, 1982, Vol. 121, No. 1, page 7.These publications do not suggest any carrier systems other than thespecific N-methyl and N-benzyl nicotinic acid-type carriers disclosed inthe Science publication. Other classes of drugs as well as a fewspecific drugs are mentioned as possible candidates for derivatization;for example, steroid hormones, cancer drugs and memory enhancers areindicated as targets for possible future work, as are enkephalins, andspecifically, dopamine and testosterone. The publications do not suggesthow to link such drugs to the carrier except possibly when the drugs aresimple structures containing a single NH₂ or, perhaps, simple structurescontaining a single OH, of the primary or secondary type, as is the casewith phenylethylamine or testosterone. There is, for example, nosuggestion of how one of ordinary skill in the art would form adrug-carrier combination when the drug has a more complicated chemicalstructure than phenylethylamine, e.g., dopamine or an enkephalin. Forfurther details concerning the work with phenylethylamine, dopamine andtestosterone, see also Bodor et al, J. Med. Chem., Vol. 26, March 1983,pp. 313-317; Bodor et al, J. Med. Chem., Vol. 26, April 1983, pp.528-534; Bodor et al, Pharmacology and Therapeutics, Vol. 19, No. 3, pp.337-386 (April 1983); Bodor et al, Science, Vol. 221, July 1983, pp.65-67; and Bodor et al, J. Pharm. Sci., Vol. 73, No. 3, March 1984, pp.385-388.

In view of the foregoing, it is apparent that an acutely serious needexists for a truly effective, generic but nonetheless flexible, methodfor the site-specific or sustained delivery, or both, of drug species tothe brain. This need has been addressed by the earlier copendingapplications referred to hereinabove, and especially by the Ser. Nos.379,316 and 516,382, now U.S. Pat. Nos. 4,479,932 and 4,540,564,respectively, which provide such a generic method for site-specific,sustained delivery of drugs to the brain utilizing adihydropyridine⃡pyridinium salt type of redox carrier system. Accordingto those applications, a drug (typically having a reactive hydroxyl,carboxyl or amino group) can be coupled to a dihydropyridine⃡pyridiniumcarrier; the lipoidal dihydro form of the drug-carrier system readilycrosses the blood-brain barrier; the dihydropyridine moiety is thenoxidized in vivo to the ideally inactive quaternary form, which is"locked in" the brain, while it is facilely eliminated from the generalcirculation; enzymatic cleavage of the "locked in" quaternary effects asustained delivery of the drug itself to the brain, to achieve thedesired biological effect. The aforementioned earlier applicationsdisclose a variety of specific carriers for use in site-specific drugdelivery. Nevertheless, a need still exists for additional specificcarriers which incorporate the dihydropyridine⃡pyridinium salt redoxsystem and which can be coupled to drugs to deliver them in a sustained,site-specific manner. Such additional carriers would enhance theflexibility of the present inventor's dihydropyridine/pyridinium saltredox carrier system as described in his earlier copending applications,since new dihydropyridine/pyridinium salt redox carriers could be usedto modify the rate of oxidation of the dihydro form to the correspondingquaternary and/or to modify the rate of release of the drug itself fromthe "locked in" quaternary form. This need is met by the inventiondescribed herein.

SUMMARY OF THE INVENTION

It has now been found that applicant's chemical delivery system asdescribed in his earlier applications can be expanded to include use ofnew classes of dihydropyridine⃡pyridinium salt type redox carriers; andthat this expanded system is well suited for an effective site-specificand/or sustained and/or enhanced delivery of drugs to the brain.

In one aspect, the present invention thus provides, as an effective drugdelivery system, novel compounds of the formula ##STR6## and thenontoxic pharmaceutically acceptable salts thereof, wherein D is theresidue of a centrally acting drug containing at least one reactivefunctional group selected from the group consisting of amino, hydroxyl,mercapto, carboxyl, amide and imide, said residue being characterized bythe absence of a hydrogen atom from at least one of said reactivefunctional groups in said drug; n is a positive integer equal to thenumber of said functional groups from which a hydrogen atom is absent;and [DHC] is the reduced, biooxidizable, blood-brain barrier penetratinglipoidal form of a dihydropyridine⃡pyridinium salt redox carrier, saidcarrier comprising a bivalent radical of the formula ##STR7## whereinthe alkylene group can be straight or branched and can contain 1 to 3carbon atoms; R_(o) is a radical identical to the corresponding portionof a natural amino acid; and p is 1 or 2, provided that, when p is 2,then the alkylene groups can be the same or different and the R_(o)radicals can be the same or different; said bivalent radical being sopositioned that the terminal carbonyl function of the bivalent radicalis linked to the drug residue while the terminal amino function of thebivalent radical is linked to the remaining portion of the carriermoiety.

In another aspect, the present invention provides, as novel chemicalintermediates to the compounds of formula (I), the quaternary salts ofthe formula ##STR8## wherein D and n are as defined with formula (I);[QC⁺ ] is the hydrophilic, ionic pyridinium salt form of adihydropyridine⃡pyridinium salt redox carrier, said carrier comprising abivalent radical of the formula ##STR9## wherein R_(o), p and thealkylene group are as defined with formula (I), said bivalent radicalbeing positioned as in formula (I); Y⁺ is the anion of apharmaceutically acceptable organic or inorganic acid; t is the valenceof the acid anion; and q is the number which when multiplied by t isequal to n. The pyridinium salts of formula (II) are not only chemicalintermediates to the corresponding compounds of formula (I) but alsorepresent the form of the present chemical delivery system which is"locked in" the brain following administration of the formula (I)dihydro derivatives.

In yet another aspect, the present invention provides a method forspecific and/or target enhanced delivery to the brain of a wide varietyof centrally acting drug species, such brain-specific drug deliverybeing effected via the bidirectional transport of the drug species intoand out of the brain by means of the particulardihydropyridine⃡pyridinium salt carrier type redox system, (I)⃡(II). Thus,the lipoidal form (I) readily crosses the blood-brain barrier; oxidationof (I) in vivo affords the corresponding pyridinium salt (II) which,because of its hydrophilic, ionic nature, is "locked in" the brain,while it is readily eliminated from the general circulation; andenzymatic cleavage of the "locked in" quaternary effects sustaineddelivery of the drug itself. The new carriers encompassed by formulas(I) and (II) herein make it possible to modify the rate of oxidation of(I) to (II). Moreover, these new carriers allow more controllableenzymatic cleavage of (II) to release the drug itself, because they area better substrate for peptidase and esterase than are the correspondingcarriers in which a bivalent radical of the formula ##STR10## as definedhereinabove does not link the drug to the remainder of the carriermoiety. Cleavage of the bond between the drug portion of the moleculeand the terminal carbonyl function of the bivalent radical leads torelease of the drug, while the carrier portion of the molecule may beeliminated as such or further cleaved between the terminal aminofunction of the bivalent radical and the remainder of the carrier. Thecarrier itself is composed of portions having low toxicity; thus,enhanced drug efficacy and decreased toxicity as compared toadministration of the drug itself can be expected from use of thepresent invention. Moreover, consistent herewith, there is providedenhanced site-specific and sustained delivery to the brain of a widevariety of centrally acting agents which are not themselves able topenetrate the blood-brain barrier to any considerable extent.

DETAILED DESCRIPTION OF THE INVENTION

More particularly, in accord with the present invention, the followingdefinitions are applicable:

The term "drug" as used herein means any substance intended for use inthe diagnosis, cure, mitigation, treatment or prevention of disease orin the enhancement of desirable physical or mental development andconditions in man or other animal.

The term "lipoidal" as used herein designates a carrier moiety which islipid-soluble or lipophilic.

The expression "non-toxic pharmaceutically acceptable salts" as usedherein generally includes the non-toxic salts of products of theinvention of structure (I) hereinabove formed with non-toxic,pharmaceutically acceptable inorganic or organic acids of the generalformula HY. For example, the salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, fumaric, methanesulfonic,toluenesulfonic and the like. The expression "anion of apharmaceutically acceptable organic or inorganic acid" as used herein,e.g. in connection with structure (II) above, is intended to includeanions of such HY acids.

It will be appreciated from the foregoing that a compound of formula (I)may be administered as the free base or in the form of a non-toxicpharmaceutically acceptable salt thereof, i.e. a salt which can berepresented by the formula ##STR11## wherein D, [DHC], n and HY aredefined as before; and that, regardless of the actual form in which thecompound is administered, it will be converted in vivo to a quaternarysalt of formula (II), the anion Y⁻ being present in vivo. It is notnecessary that the anion be introduced as part of the compoundadministered. Indeed, even when the compound of formula (I) is used inits salt form, the anion of the formula (II) compound in vivo is notnecessarily the same as that present in the formula (I) compound. Infact, the exact identity of the anionic portion of the compound offormula (II) is immaterial to the in vivo transformation of (I) to (II).

In the expression "at least one reactive functional group selected fromthe group consisting of amino, hydroxyl, mercapto, carboxyl, amide andimide" as used herein, the designated reactive functional groups havethe following meanings:

The word "amino" means a primary or secondary amino function, i.e. --NH₂or --NHR. The secondary amino function is also represented herein as--NH--, particularly since the exact identity of the R portion of --NHRis immaterial, R being a part of the drug residue D itself which is leftunchanged by this invention.

The word "hydroxyl" means an --OH function.

The word "carboxyl" means a --COOH function.

The word "mercapto" means an --SH function.

The word "amide" means a carbamoyl (--CONH₂) or substituted carbamoyl(--CONHR) functional group or a sulfamoyl (--SO₂ NH₂) or substitutedsulfamoyl (--SO₂ NHR) functional group. The --CONHR group may also berepresented herein as --CONH--, since the exact identity of the Rportion of --CONHR is immaterial, R being a part of the drug residue Ditself which is left unchanged by this invention. Similarly, the --SO₂NHR group may also be represented herein as --SO₂ NH-- since theidentity of R is likewise immaterial, R being part of the drug residue Ditself which is left unchanged by this invention.

The word "imide" means a functional group having the structure ##STR12##that is, the structure which characterizes imides (i.e. compounds havingsuccinimide-type, or phthalimide-type structures and so forth).

The expression "R_(o) is a radical identical to the correspondingportion of a natural amino acid" is believed to be self-explanatory.Thus, for example, R_(o) can be hydrogen, as in glycine; methyl, as inalanine; --CH(CH₃)₂, as in valine; --CH₂ --CH(CH₃)₂, as in leucine; --##STR13## as in isoleucine; ##STR14## as in phenylalanine; ##STR15## asin tryptophan; --CH₂ OH, as in serine; --CHOH--CH₃, as in threonine;--(CH₂)₂ --SCH₃, as in methionine; --CH₂ --CONH₂, as in asparagine;--CH₂ CH₂ --CONH₂, as in glutamine; ##STR16## as in tyrosine; --CH₂ SH,as in cysteine; --CH₂ COOH, as in aspartic acid; and --CH₂ CH₂ COOH, asin glutamic acid. The expression "natural amino acid" as used hereindoes not encompass dopa or L-DOPA. Preferred amino acids encompassed bythe R_(o) term include glycine, alanine, valine, leucine, phenylalanine,isoleucine, methionine, asparagine and glutamine.

By "centrally acting" drug species, active agent or compound as utilizedherein, there is of course intended any drug species or the like, asignificant (usually, principal) pharmacological activity of which isCNS and a result of direct action in the brain.

Exemplary such centrally acting drug species are the CNS-amines andother nervous system agents, whether sympathetic or parasympathetic,e.g., phenylethylamine (a stimulant), dopamine (a neurotransmitter anddopa-minergic agent used, e.g. in the treatment of Parkinsonism orhyperprolactinemia), tyramine (a stimulant), L-DOPA (a dopamineprecursor, used, for example, in the treatment of Parkinsonism); musclerelaxants, tranquilizers and antidepressants, e.g., benzodiazepinetranquilizers such as oxazepam and phenothiazine tranquilizers such ascarphenazine, fluphenazine and the like; mild and strong analgesics andnarcotics; sedatives and hypnotics; narcotic antagonists; vascularagents; stimulants; anesthetics; antiepileptic and anticonvulsant drugsgenerally, including hydantoins such as phenytoin and ethotoin;barbituates such phenobarbital; hormones, such as the steroid hormones,e.g., estradiol, testosterone, 17 α-ethynyl testosterone (ethisterone),and the like (recent studies on histological mapping ofhormone-sensitive and specific steroid binding cells in the brain haveunderscored the importance of the steroid action in the brain on sexualbehavior); amphetamine-like drugs; anticancer and anti-Parkinsonismagents; antihypertensives; agents to enhance learning capacity and thememory processes, including treatment of dementias, such as Alzheimer'sdisease; antibacterials; growth promoters; centrally active hypotensiveagents; centrally acting prostaglandins; diagnostic agents, such asradiopharmaceuticals ; monoamine oxidase (MAO) inhibitor drugs; and anylike centrally acting compounds.

Other illustrative ultimate species of centrally active drug entitiesare: amphetamine, dextroamphetamine, levamphetamine, aletamine,cypenamine, fencamfamin, fenozolone, zylofuramine, methamphetamine,phenmetrazine and phentermine, which are sympathomimetic amines/cerebralstimulants and appetite suppressants; etryptamine, a cerebral stimulant;codeine, oxycodone, pentazocine, anileridine, hydromorphone, morphineand oxymorphone, which are natcotic analgesics; desipramine,nortriptyline, octriptyline, maprotiline, opipramol and protriptyline,which are cerebral stimulants/tricyclic antidepressants of thedibenzazapine-type used, e.g., in endogenous depressions; clonidine andmethyldopa, which are sympatholytic agents used, e.g., in hypertension;biperiden, cycrimine and procyclidine, which are centrally actinganticholinergics; tranylcypromine, a sympathomimetic cerebralstimulant/MAO inhibitor and antidepressant; acetophenazine,carphenazine, fluphenazine, perphenazine and piperacetazine, which arephenothiazine-type tranquilizers; benzoctamine, a sedative/musclerelaxant which structurally is an analogue of the phenothiazinetranquilizers; chlordiazepoxide, clorazepate, nitrazepam and temazepam,which are benzodiazepine-type tranquilizers; noracymethadol, a narcoticanalgesic of the methadone-type; piminodine, a narcotic analgesic of themeperidine type; tracazolate, a sedative/hypnotic; tileramine, ananticonvulsant; prizidilol, a centrally acting hypotensive; sulpiride,an antidepressant/psychotropic; haloperidol and clopenthixol, which aretranquilizers; norepinephrine, a sympathetic stimulant/adrenergic agent;nalorphine and naloxone, narcotic antagonists; hydralazine, ahypotensive; ethotoin, phenobarbital and aminoglutethimide,anticonvulsants; epinephrine, an adrenergic agent; ethamivan, amedullary stimulant; bemegride, a barbiturate antagonist; amiphenazole,a stimulant; iopydol, iodopyracet, iodouppurate (o-iodohippuric acid),iodamide and iopanoic acid, which are radiodiagnostics; ephedrine;pseudoephedrine, oxymetazoline and phenylephrine, which aresympathomimetic amines and decongestants; estradiol, estrone andestriol, the natural estrogens; amoxicillin, oxacillin, carbenicillin,benzylpenicillin, phenoxymethylpenicillin, methicillin, nafcillin,ticarcillin, bacampicillin, epicillin, hetacillin, pivampicillin, themethoxymethylester of hetacillin and ampicillin, which arepenicillin-type antibiotics; amobarbital, a sedative; trihexyphenidyl, acentrally acting anticholinergic; hydroxyzine, a tranquilizer;chlortetracycline, demeclocycline, minocycline, doxycycline,oxytetracycline, tetracycline and methacycline, which aretetracycline-type antibiotics; clindamycin, lincomycin, nalidixic acid,oxolinic acid and phenazopyridine, antibacterials/antibiotics;bromazepam, demoxepam and lorazepam, benzodtazeptne tranquilizers;phenytoin, an anticonvulsant; glutethimide, a mild hypnotic/sedative;bethanidine and guanethidine, hypotensives/sympatholytics; captopril, ahypotensive; methyprylon, a mild hypnotic; amedalin, bupropion,cartazolate, daledalin, difluanine, fluoxetine and nisoxetine, which arecerebral stimulants; dicloxacillin, a penicillin-type antibacterial;butalbital, a barbiturate sedative; γ-vinyl GABA and γ-acetylenic GABA,derivatives of the neurotransmitter GABA for possible use in epilepsy;valproic acid and its metabolites such as 5-hydroxy-2-n-propylpentanoicacid, 4-hydroxy-2-n-propylpentanoic acid and3-hydroxy-2-n-propylpentanoic acid, also for use as anticonvulsants;valpromide, a valproic acid derivative for use as an anticonvulsant;apomorphine, a narcotic depressant/emetic, which has been used in thetreatment of photosensitive epilepsy; pholcodine, a narcoticantitussive; methotrexate, mitoxantrone, podophyllotoxin derivatives(etopside, teniposide), doxorubicin, daumamycin and cyclophosphamide,anticancer/antitumor agents; methylphenidate, a stimulant; thiopental,an anesthetic; ethinyl estradiol and mestranol, estrogens; meptazinol,cyclazocine, phenazocine, profadol, metopon, drocode and myfadol, whichare narcotic analgesics; buprenorphine, nalbuphine, butorphanol,levallorphan, naltrexone, alazocine, oxilorphan and nalmexone, which arenarcotic antagonists or agonist-antagonists; norgestrel andnorethindrone, progestins; cephalothin, cephalexin, cefazolin,cefoxitln, moxalactam, ceforanide, cefroxadine and cephapirin,cephalosporin antibiotics; atenolol, propranolol, nadolol, timolol andmetoprolol, β-blockers/hypotensives; sulfadiazine and other sulfonamideantibiotics; ribavarin and acyclovir, antiviral agents; chlorambucil andmelphalan, nitrogen mustard-type antlcancer/antitumor agents;methotrexate and aminopterin, which are folic acid antagonist-typeanticancer/antitumor agents; platinum coordination complexes, i.e.cisplatin analogue-type anticancer/antitumor agents; dactinomycin andmitomycin C, used in cancer chemotherapy; thioguanine, apurine/pyrimidine antagonist used in cancer treatment; vincristine andvinblastine, anticancer alkaloids; hydroxyurea and DON, anticancer ureaderivatives; N,N'-bis(dichloracetyl)-1,8-octamethylenediamine(fertilysin), an agent for male fertility inhibition; levorphanol, anarcotic, analgesic; benzestrol and diethylstilbestrol, syntheticestrogens; ethyl β-carboline-3-carboxylate, a benzodiazepine antagonist;furosemide, a diuretic/antihypertensive; dipyridamole and nifedipine,coronary vasodilators; progabide, a GABA-agonist and prodrug of GABA.Yet other ultimate species include nonsteroidal antiinflammatoryagents/non-narcotic analgesics, e.g., propionic acid derivatives, aceticacid derivatives, fenamic acid derivatives and biphenylcarboxylic acidderivatives. Specific NSAID's/nonnarcotic analgesics contemplated foruse herein include ibuprofen, naproxen, flurbiprofen, zomepirac,sulindac, indomethacin, fenbufen, fenoprofen, indoprofen, ketoprofen,fluprofen, bucloxic acid, tolmetin, alclofenac, fenclozic acid,ibufenac, flufenisal, pirprofen, flufenamic acid, mefenamic acid,clonixeril, clonixin, meclofenamic acid, flunixin, diclofenac,carprofen, etodolac, fendosal, prodolic acid, sermetacin, indoxole,tetrydamine, diflunisal, naproxol, piroxicam, metazamide, flutiazin andtesicam.

Preferred classes of centrally acting drugs for use herein are thecentral neurotransmitters, steroids, anticancer and antitumor agents,antiviral agents, tranquilizers, memory enhancers, hypotensives,sedatives, antipsychotics and cerebral stimulants (especially tricyclicantidepressants). Among the neurotransmitters, there can be mentionedcatecholamines, such as doramine, norepinephrine and epinephrine;serotonin, histamine and tryptamine. Among the steroids, there can bementioned antiinflammatory adrenal cortical steroids such ashydrocortisone, betamethasone, cortisone, dexamethasone, flumethasone,fluprednisolone, meprednisone, methyl prednisolone, prednisolone,prednisone, triamcinolone, cortodoxone, fludrocortisone, flurandrenoloneacetonide (flurandrenolide), paramethasone and the like; male sexhormones (androgens), such as testosterone and its close analogues, e.g.methyl testosterone (17-methyltestosterone); and female sex hormones,both estrogens and progestins, e.g., progestins such as norgestrel,norethindrone, norethynodrel, ethisterone, dimethisterone,allylestrenol, cingestol, ethynerone, lynestrenol, norgesterone,norvinisterone, ethynodiol, oxogestone and tigestol, and estrogens suchas ethinyl estradiol, mestranol, estradiol, estriol, estrone andquinestrol and the like. Among the anticancer and antitumor agents,there can be mentioned Ara-AC, pentostatin (2'-deoxycoformycin), Ara-C(cytarabine), 3-deazaguanine, dihydro-5-azacytidine, tiazofurin,sangivamycin, Ara-A (vidarabine), 6-MMPR, PCNU, spiromustine,btsbenzimtdazole, L-alanosine, DON (6-diazo-5-oxo-L-norleucine), L-ICRF,trimethyl TMM, 5-methyltetrahydrohomofolic acid, glyoxylic acidsulfonylhydrazone, DACH, SR-2555, SR-2508, desmethylmisonidazole,mitoxantrone, menogarol, aclacinomycin A, phyllanthoside, bactobolin,aphidocolin, homoharringtonine, levonantradol, acivicin, streptozotocin,hydroxyurea, chlorambucil, cyclophosphamide, uracil mustard, melphalan,5-FUDR (floxuridine), vincristine, vinblastine, cytosine arabinoside,6-mercaptopurine, hioguanine, 5-azacytidne, methotrexate, adriamycin(doxorubicin), daunomycin (daunorubicin), largomycine polypeptide,aminopterin, dactinomycin, mitomycin C and podophyllotoxin derivatives,such as etoposide (VP-16) and teniposide. Among the antiviral agents,there can be mentioned ribavarin; acyclovir (ACV); amantadine (also ofpossible value as an anti-Parkinsonism agent); diarylamidines such as5-amidino-2-(5-amidino-2-benzofuranyl)indole and4',6-diimidazolino-2-phenylbenzo(b)thiophene; 2-aminoxazoles such as2-guanidino-4,5-di-n-propyloxazole and 2-guanidino-4,5-diphenyloxazole;benzimidazole analogues such as the syn and anti isomers of6-[[(hydroxyimino)phenyl]-methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine;bridgehead C-nucleosides such as5,7-dimethyl-2-β-D-ribofuranosyl-s-triazole(1,5-a)pyrimidine; glycosidessuch as 2-deoxy-D-glycose, glycosamine, 2-deoxy-2-fluoro-D-mannose and6-amino-6-deoxy-D-glucose; phenyl glucoside derivatives such asphenyl-6-chloro-6-deoxy-β-D-glycopyranoside;(S)-9-(2,3-dihydroxy-propyl)adenine; 6-azauridine; idoxuridine;trifluridine; BDVU (bisdihydroxyvinyluridine); and5,6-dichloro-1-β-D-ribofuranosylbenzimidazole. Among the tranquilizers,there can be mentioned benzodiazepine tranquilizers such as oxazepam,lorazepam, chlordiazepoxide, bromazepam, chlorazepate, nitrazepam andtemazepam; hydantoin-type tranquilizers/anticonvulsants such asphenytoin, ethotoin and mephenytoin; phenothiazine-type tranquilizerssuch as acetophenazine, carphenazine, fluphenazine, perphenazine andpiperacetazine; and others. Among the hypotensives, there can bementioned clonidine, methyldopa, bethanidine, debrisoquin, hydralazine,and guanethidine and its analogues. Among the sedatives, tranquilizersand antipsychotics, there can be mentioned the many specific compoundsof this type already disclosed above, especially the phenothiazines andbenzodiazepines and their analogues. Among the cerebral stimulants,there can also be mentioned the many specific compounds set forthhereinabove, particularly the sympathomimtic amine-type cerebralstimulants and the tricyclic antidepressants, especially preferredtricyclics being the dibenzazepines and their analogues.

Also illustrative of the centrally acting drug species contemplated bythis invention are centrally active metabolites of centrally actingdrugs. Such metabolites are typified by hydroxylated metabolites oftricyclic antidepressants, such as the E- and Z-isomers of10-hydroxynortriptyline, 2-hydroxyimipramine, 2-hydroxydesipramine and8-hydroxychlorimipramine; hydroxylated metabolites of phenothiazinetranquilizers, e.g. 7-hydroxychlorpromazine; and desmethyl metabolitesof N-methyl benzodiazepine tranquilizers, e.g. desmethyldiazepam. OtherCNS active metabolites for use herein will be apparent to those skilledin the art, e.g. SL75102, which is an active metabolite of progabide, aGABA agonist. Typically, these CNS active metabolites have beenidentified as such in the scientific literature but have not beenadministered as drugs themselves. In many cases, the active metabolitesare believed to be comparable in CNS activity to their parent drugs;frequently, however, the metabolites have not been administered per sebecause they are not themselves able to penetrate the blood-brainbarrier.

As indicated hereinabove, diagnostic agents, includingradiopharmaceuticals, are encompassed by the expression "centrallyacting drug" or the like as used herein. Any diagnostic agent which canbe derivatized to afford a compound of formula (I) which will penetratethe BBB and concentrate in the brain in its quaternary form (II) and canbe detected therein is encompassed by this invention. The diagnostic maybe "cold" and be detected by X-ray (e.g. radiopaque agents) or othermeans such as mass spectrophotometry, NMR or other non-invasivetechniques (e.g., when the compound includes stable isotopes such as C13, N 15, O 18, S 33 and S 34). The diagnostic alternatively may be"hot", i.e. radiolabeled, such as with radioactive iodine (I 123, I 125,I 131) and detected/imaged by radiation detection/imaging means. Typical"cold" diagnostics for derivation herein include o-iodohippuric acid,iothalamic acid, iopydol, iodamide and iopanoic acid. Typicalradiolabeled diagnostics include diohippuric acid (I 125, I 131),diotyrosine (I 125, I 131), o-iodohippuric acid (I 131), iothalamic acid(I 125, I 131), thyroxine (I 125, I 131), iotyrosine (I 131) andiodometaraminol (I 123), which has the structural formula ##STR17## Inthe case of diagnostics, unlike the drugs which are for treatment orprevention of disease, the "locked in" quaternary form will be the formthat is imaged or detected, not the original diagnostic itself.Moreover, any of the centrally acting drugs encompassed by thisinvention which are intended for the treatment or prevention of medicaldisorders or the like which can be radiolabeled, e.g. with aradioisotope such as iodine, or labeled with a stable isotope, can thusbe converted to a diagnostic for use herein. Put another way, anycompound of formula (I) of this invention which can have incorporatedinto its structure such a radioactive or stable isotope [either directlyor through incorporation of the isotope into the structure of thecorresponding compound of formula (IX)] can be used for diagnosticpurposes.

Specifically excluded from the scope of the expression "centrallyacting" drug species, compound or the like as used herein are aminoacids, small peptides, such as di-, tri-, tetra- and pentapeptides, andother small 2-20 amino acid unit containing peptides, e.g. enkephalinsand endorphins, as well as larger peptides. The specifically excludedamino acids include tryptophan, GABA, glycine, glutamic acid, tyrosine,aspartic acid and other natural amino acids such as those typicallyincorporated into protein. However, dopa, or L-DOPA, is not classifiedas an amino acid according to this application or its parent Ser. Nos.379,316 and 516,382, now U.S. Pat. Nos. 4,479,932 and 4,540,564,respectively, but rather as a CNS amine and dopaminergic agent used, forexample, in the treatment of Parkinsonism; thus, L-DOPA is not intendedto be excluded from derivation according to this invention, but on thecontrary is a particularly significant centrally acting drug encompassedhereby.

It will be apparent from the known structures of the many drug speciesexemplified above, that in many cases the selected drug will possessmore than one reactive functional group, and, in particular, that thedrug may contain hydroxyl or carboxyl or amino or other functionalgroups in addition to the groups to which the carrier will be linked andthat these additional groups will at times benefit from being protectedduring synthesis and/or during administration. The nature of suchprotection is described in more detail below. Obviously, such protecteddrug species are encompassed by the definition of "drug" set forthhereinabove.

The expression "hydroxyl protective group" as used hereinbelow isintended to designate a group which is inserted in place of the hydrogenatom(s) of an OH group or groups in order to prevent prematuremetabolism of said OH group or groups prior to the compound's reachingthe desired site in the body. Typical hydroxyl protective groupscontemplated by the present invention are acyl groups and carbonates.

When the hydroxyl protective group is acyl (i.e., when it is an organicradical derived from a carboxylic acid by removal of the hydroxylgroup), it preferably represents an acyl radical select ed from thegroup consisting of alkanoyl having 2 to 8 carbon atoms; alkenoyl havingone or two double bonds and 3 to 8 carbon atoms; ##STR18## wherein thecycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two orthree; phenoxyacetyl; pyridinecarbonyl; and ##STR19## wherein r is zero,one, two or three and phenyl is unsubstituted or is substituted by 1 to3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbonatoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms oralkanoylamino having 2 to 6 carbon atoms.

When the acyl group is alkanoyl, there are included both unbranched andbranched alkanoyl, for example, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl 2-methylbutanoyl, pivalyl (pivaloyl),3-methylpentanoyl, 3,3 -dimethylbutanoyl, 2,2-dimethylpentanoyl and thelike. Pivalyl, isobutyryl and isovaleryl are especially preferred.

When the acyl group is alkenoyl, there are included, for example,crotonyl, 2,5-hexadienoyl and 3,6-octadienoyl.

When the acyl group is ##STR20## there are included cycloalkanecarbonyland cycloalkanealkanoyl groups wherein the cycloalkane portion canoptionally near 1 or 2 alkyl groups as substituents, e.g.cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl, cyclopropaneacetyl,α-methylcyclopropaneacetyl, 1-methylcyclopropaneacetyl,cyclopropanepropionyl, α-methylcyclopropanepropionyl,2-isobutylcyclopropanepropionyl, cyclobutanecarbonyl,3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl,2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclopentanecarbonyl,cyclohexaneacetyl, cyclohexanecarbonyl, cycloheptanecarbonyl andcycloheptanepropionyl. Cyclohexanecarbonyl is especially preferred.

When the acyl group is pyridinecarbonyl, there are included picolinoyl(2-pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl) and isonicotinoyl(4-pyridinecarbonyl).

When the acyl group is ##STR21## there are included, for example,benzoyl, phenylacetyl, α-phenylpropionyl, β-phenylpropionyl, p-toluyl,m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl,3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl,m-methylphenylacetyl, p-isobutylphenylacetyl, β(p-ethylphenyl)propionyl,p-anisoyl, m-anisoyl, o-anisoyl, m-isopropoxybenzoyl,p-methoxyphenylacetyl, m-isobutoxyphenylacetyl, m-diethylaminobenzoyl,3-methoxy-4-ethoxybenzoyl, 3,4,5-trimethoxybenzoyl,p-dibutylaminobenzoyl, 3,4-diethoxyphenylacetyl,β-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl,p-chlorobenzoyl, p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl,2,4,6-trichlorobenzoyl, p-chlorophenylacetyl,α-(m-bromophenyl)propionyl, p-trifluoromethylbenzoyl,2,4-di(trifluoromethyl)benzoyl, m-trifluoromethylphenylacetyl,β-(3-methyl-4-chlorophenyl)propionyl, p-dimethylaminobenzoyl,p-(N-methyl-N-ethylamino)benzoyl, o-acetamidobenzoyl,m-propionamidobenzoyl, 3-chloro-4-acetamidophenylacetyl,p-n-butoxybenzoyl, 2,4,6-triethoxybenzoyl,β-(p-trifluoromethylphenyl)propionyl, 2-methyl-4-methoxybenzoyl,p-acetamidophenylpropionyl and 3-chloro-4-ethoxybenzoyl.

When the hydroxyl protective group is a carbonate grouping, it has thestructural formula ##STR22## i.e., it is an organic radical which can beconsidered to be derived from a carbonic acid by removal of the hydroxylgroup from the COOH portion. Y' preferably represents alkyl having 1 to7 carbon atoms; alkenyl having one or two double bonds and 2 to 7 carbonatoms;

    cycloalkyl--C.sub.r H.sub.2r --

wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero,one, two or three; phenoxy; 2-, 3-, or 4-pyridyl; or

    phenyl--C.sub.r H.sub.2r --

wherein r is zero, one, two or three and phenyl is unsubstituted or issubstituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxyhaving 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms. Mostpreferably, Y' is C₁ -C₇ alkyl, particularly ethyl or isopropyl.

Similarly, the expression "carboxyl protective group" as usedhereinbelow is intended to designate a group which is inserted in placeof the hydrogen atom(s) of a COOH group or groups in order to preventpremature metabolism of said COOH group or groups prior to thecompound's reaching the desired site in the body. Typical carboxylprotective groups are the groups encompassed by Y' above, especially C₁-C₇ alkyl, particularly ethyl, isopropyl and t-butyl. While such simplealkyl esters and the like are often useful, other carboxyl protectinggroups may be selected in order to achieve greater control over the rateof in vivo hydrolysis of the ester back to the acid and thus enhancedrug delivery. To that end, carboxyl protecting groups such as thefollowing may be used to replace the hydrogen of the --COOH group:##STR23## wherein alk is C₁ -C₆ straight or branched alkylene and thealkyl radical is straight or branched and contains 1 to 7 carbon atoms##STR24##

The expression "amino protective group" as used hereinbelow is intendedto designate a group which is inserted in place of the hydrogen atom(s)of an amino group or groups in order to prevent unwanted reaction of theamino function(s) during chemical synthesis. Such protective groups arewell-known in the art and include t-butoxycarbonyl and carbobenzoxy(i.e. benzyloxycarbonyl). Other appropriate amino protective groups willbe apparent to those skilled in the art. Unlike the instant hydroxyl andcarboxyl protective groups described above, which not only preventunwanted chemical reaction but also protect those hydroxyl and carboxylfunctions from premature metabolism in vivo, the amino protective groupsare primarily intended for use during synthesis and are typicallyremoved by well-known procedures at an appropriate stage of thesynthetic pathway after they have achieved their protective function andare no longer needed. Occasionally, however, an amino protectivefunction will be retained in the compound of formula (I) to also protectthe amino group in vivo.

In accord with the present invention, the sustained delivery of a drugto the brain in sufficient concentrations to achieve the desiredpharmacological effect can be accomplished with much lowerconcentrations in the peripheral circulation and other tissues. Thepresent invention of course will allow such treatment of any otherorgans or glands in which sufficient drug accumulates. Thus, forexample, it is expected that the quaternary form (II) which is locked inthe brain will be locked in the testes as well. See my earlier copendingapplication Ser. No. 475,493 now U.S. Pat. No. 4,622,218.

The novel chemical delivery system of this invention begins with thepreparation of the novel quaternary intermediates of formula (II). Thepreparation of those intermediates will be tailored to the particulardrug portion and carrier portion to be combined, and especially to thenature of the chemical bond between them, e.g. whether the linkage is anester or amide linkage, as well as to the presence or absence of ocherreactive functional groups (amino, mercapto, carboxyl, hydroxy) ineither the drug or carrier portion. Typically, if such other reactivegroups are present, they are found in the drug portion or in the R_(o)portion of the carrier. In any event, when such groups are present andit is desired to protect them, a step that introduces appropriateprotecting groups can be incorporated at a suitable stage of thesynthetic pathway. Typical protective groups are well known in the artand have been defined hereinabove. When carbonate protecting groups foralcoholic hydroxyl radicals are desired, the step of introducing theprotecting groups will involve reacting the alcohol with a halocarbonateof the type ROCOCl or ROCOBr (formed by reaction of ROH with COCl₂ orCOBr₂, R typically being lower alkyl). For acyl protecting groups, thealcoholic hydroxyl is reacted with an acyl halide RCl or RBr, R being--COCH₃ or --COC(CH₃)₃. Yet other reaction schemes and reactants will bereadily apparent to those skilled in the art as will the appropriatemeans for removing such protective groups after they have achieved theirfunction and are no longer needed. As already explained above, carboxyland hydroxyl protecting groups are typically retained in the compoundsof formula (I) and (II) rather than being removed, so that they canperform their protective function in vivo as well.

In forming the intermediates of formula (II), at least one amino,hydroxy,l mercapto, carboxyl, amide or imide group in a drug will bebonded to [QC]⁺, the hydrophilic, ionic pyridinium salt form of adihydropyridine⃡pyridinium salt redox carrier comprising a divalentradical as defined hereinabove.

It too will be appreciated that by "dihydropyridine carrier" or "[DHC]",there is intended any nontoxic carrier moiety comprising, containing orincluding the dihydropyridine nucleus, whether or not a part of anylarger basic nucleus, and whether substituted or unsubstituted, the onlycriteria therefor being (1) capacity for BBB penetration and in vivooxidation thereof to the corresponding quaternary pyridinium saltcarrier [QC⁺ ], and (2) incorporation therein of the bivalent radical##STR25## wherein the structural variables are defined as hereinabove.As aforesaid, the ionic pyridinium salt drug/carrier prodrug entityD--QC⁺ ] which results from such in vivo oxidation is prevented fromefflux from the brain, while elimination from the general circulation isaccelerated. Subsequently, the bond coupling the drug species to thequaternary carrier [QC⁺ ] is metabolically cleaved which results insustained delivery of the drug in the brain and facile elimination ofthe carrier moiety [QC⁺ ]. And the cleavage of the quaternary compound(II) to sustainedly deliver the drug species in the brain withconcomitant facile elimination of the carrier moiety [QC⁺ ] ischaracteristically enzymatic cleavage, e.g., by esterase, peptidase,amidase, cholinesterase or hydrolytic enzyme, albeit any type of inbrain cleavage which might result, whether enzymatic, metabolic orotherwise, of course remains within the ambit of this invention. Thus,the drug release rate controlling parameter of the compounds of thisinvention is imparted via the clearable bonding between drug andcarrier, and not by any release rate controlling substituent(s).

Dihydropyridine⃡pyridinium salt redox carrier moieties for use hereininclude the following quaternaries and the corresponding dihydro forms:

(1) For linkage to a drug having at least one hydroxyl or mercapto orprimary or secondary amino functional grouping, replacing a hydrogenatom from at least one of said functional groupings with one of thefollowing [QC⁺ ] groupings: ##STR26## wherein alkylene, R_(o) and p areas defined with formula (I) hereinabove; R₁ is C₁ -C₇ alkyl, C₁ -C₇haloalkyl or C₇ -C₁₀ aralkyl; R₃ is C₁ to C₃ alkylene; X is --CONR'R"wherein R' and R", which can be the same or different, are each H or C₁-C₇ alkyl, or X is --CH═NOR"' wherein R"' is H or C₁ -C₇ alkyl; thecarbonyl-containing groupings in formulas (a) and (c) and the Xsubstituent in formula (b) can each be attached at the 2, 3 or 4position of the pyridinium ring; the carbonyl-containing groupings informulas (d) and (f) and the X substituent in formula (e) can each beattached at the 2, 3 or 4 position of the quinolinium ring; and thecarbonyl-containing groupings in formulas (g) and (j) and the Xsubstituent in formula (h) can each be attached at the 1, 3 or 4position of the isoquinolinium ring;

(2) For, the linkage to a drug having at least one carboxyl functionalgrouping, replacing a hydrogen atom from at least one of said carboxylgroupings with one of the following [QC⁺ ] groupings:

(a) When there are one or more --COOH groups to be derivatized:##STR27## wherein alkylene, R_(o) and p are as defined with formula (I)hereinabove; Z' is C₁ -C₈ straight or branched alkylene, preferably C₁-C₃ straight or branched alkylene; Q is --O-- or--NH--; R₁ is C₁ -C₇alkyl, C₁ -C₇ haloalkyl or C₇ -C₁₀ aralkyl; R₃ is C₁ -C₃ alkylene; X is--CONR'R" wherein R' and R" , which can be the same or different, areeach H or C₁ -C₇ alkyl, or X is --CH═NOR"' where in R"' is H or C₁ -C₇alkyl; the X substituent in formula (ii) and the carbonyl-containinggroupings in formulas (i) and (iii) can each be attached at the 2, 3 or4 position of the pyridinium ring; the X substituent in formula (v) andthe carbonyl-containing groupings, in formulas (iv) and (vi) can each beattached at the 2, 3 or 4 position of the quinolinium ring; and the Xsubstituent in formula (viii) and carbonyl-containing groupings informulas (vii) and (ix) can each be attached at the 1, 3 or 4 positionof the isoquinolinium ring;

(b) Alternatively when there is only one --COOH group to be derivatized:##STR28## wherein is the skeleton of a sugar molecule; n^(iv) is apositive integer equal to the total number of --OH functions in thesugar molecule from which said skeleton is derived; n^(v) is a positiveinteger one less than the total number of --OH functions in the sugarmolecule from which said skeleton is derived; each A in each ofstructures (xii), (xiii) and (xiv) can independently be hydroxy or D',D' being the residue of a centrally acting drug containing one reactivecarboxyl functional group, said residue being characterized by theabsence of a hydrogen atom from said carboxyl functional group in saiddrug; and each R'₄ in each of structures (x) and (xi) can independentlybe hydroxy, ##STR29## wherein alkylene, R_(o) and p are defined as withformula (I); D' is defined as with structure (xii), (xiii) and (xiv); R₁is C₁ -C₇ alkyl, C₁ -C₇ haloalkyl or C₇ -C₁₀ aralkyl; and the depictedcarbonyl-containing groupings can be attached at the 2, 3 or 4 positionof the pyridinium or quinolinium ring, or at the 1, 3 or 4 position ofthe isoquinolinium ring; with the proviso that at least one R'₄ in eachof structures (x) and (xi) is ##STR30## wherein alkylene, R_(o), p andR₁ and the position of the carbonyl-containing groupings are defined asabove; and with the further proviso that when more than one of the R'₄radicals in a given compound are the aforesaid carbonyl-containinggroupings, then all such carbonyl-containing groupings in said compoundare identical.

(3) For linkage to a drug having at least one --NH-- functional groupwhich is part of an amide or imide structure or at least one low pKaprimary or secondary amine functional group, replacing a hydrogen atomfrom at least one of said functional groupings with one of the following[QC⁺ ] groupings: ##STR31## wherein alkylene, R_(o) and p are as definedwith formula (I); R₁ is C₁ -C₇ alkyl, C₁ -C₇ haloalkyl or C₇ -C₁₀aralkyl; R is hydrogen, C₁ -C₇ alkyl, C₃ -C₈ cycloalkyl, C₁ -C₇haloalkyl, furyl, phenyl, or phenyl substituted by one or more halo,lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, loweralkanoyloxy, lower haloalkyl, mono(lower alkyl)carbamoyl, di(loweralkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or loweralkylsulfonyl; R₃ is C₁ to C₃ alkylene; X is --CONR'R" wherein R' and R", which can be the same or different, are each H or C₁ -C₇ alkyl, or Xis --CH═NOR'" wherein R"' is H or C₁ -C₇ alkyl; the carbonyl-containinggroupings in formulas (k) and (m) and the X substituent in formula (1)can each be attached at the 2, 3 or 4 position of the pyridinium ring;the carbonyl containing groupings in formulas (n) and (p) and the Xsubstituent in formula (o) can each be attached at the 2, 3 or 4position of the quintolinium ring; and the carbonyl-containing groupingsin formulas (q) and (s) and the X substituent in formula (r) can each beattached at the 1, 3 or 4 position of the isoquinolinium ring. Here andthroughout this application, the expression "C₁ -C₇ haloalkyl" means C₁-C₇ alkyl substituted by one or more halogen atoms. Also here andthroughout this application, the alkyl radicals, including alkyl andalkylene portions of other radicals, can be straight or branched unlessotherwise specified.

Drugs containing secondary or tertiary hydroxyl functional groups can belinked to any of the [QC]⁺ groupings (k) through (s) above in which the##STR32## portion is derived from an aldehyde RCH₂ O capable of reactingwith said drug to form the corresponding hemiacetal, as discussed inmore detail in Method K' hereinafter.

The dihydro forms [DHC] corresponding to the aforementioned quaternariesare as follows:

(1') For Group (1) above: ##STR33## wherein alkylene, R_(o) and p are asdefined with formula (I); the dotted line in formulas (a'), (b') and(c') indicates the presence of a double bond in either the 4 or 5position of the dihydropyridine ring; the dotted line in formulas (d'),(e') and (f') indicates the presence of a double bond in either the 2 or3 position of the dihydroquinoline ring; R₁ is C₁ -C₇ alkyl, C₁ -C₇haloalkyl or C₇ -C₁₀ aralkyl; R₃ is C₁ to C₃ alkylene; X is --CONR'R"wherein R' and R", which can be the same or different, are each H or C₁-C₇ alkyl, or X is --CH═NOR"' wherein R"' is H or C₁ -C₇ alkyl; thecarbonyl-containing groupings in formulas (a') and (c') and the Xsubstituent in formula (b') can each be attached a t the 2, 3 or 4position of the dihydropyridine ring; the carbonyl-containing groupingsin formulas (d') and (f') and the X substituent in formula (e') can eachbe attached at 2, 3 or 4 position of the dihydroquinoline ring; and thecarbonyl-containing groupings in formulas (g') and (j') and the Xsubstituent in formula (h') can each be attached at 1, 3 or 4 positionof the dihydroisoquinoline ring;

(2') For Group (2) (a) above: ##STR34## wherein alkylene, R_(o) and pare as defined with formula (I) hereinabove; the dotted line in formulas(i'), (i') and (iii') indicates the presence of a double bond in eitherthe 4 or 5 position of the dihydropyridine ring; the dotted line informulas (iv'), (v') and (vi') indicates the presence of a double bondin either the 2 or 3 position of the dihydroquinoline ring; Z' is C₁ -C₈straight or branched alkylene, preferably C₁ -C₃ straight or branchedalkylene; Q is --O-- or --NH--; R₁ is C₁ -C₇ alkyl, C₁ -C₇ haloalkyl orC₇ -C₁₀ aralkyl; R₃ is C₁ -C₃ alkylene; X is --CONR'R" wherein R' andR", which can be the same or different, are each H or C₁ -C₇ alkyl; or Xis --CH═NOR"' wherein R"' is H or C₁ -C₇ alkyl; the X substituent informula (ii') and the carbonyl-containing grouping in formulas (i') and(iii') can each be attached at the 2, 3 or 4 position of thedihydropyridine ring; the X substituent in formula (v') and thecarbonyl-containing grouping in formulas (iv') and (vi') can each beattached at the 2, 3 or 4 position of the dihydroquinoline ring; and theX substituent in formula (viii') and the carbonyl-containing groupingsin formulas (vii') and (ix') can each be attached at the 1, 3 or 4position of the dihydroisoquinoline ring.

(3') For Group (2) (b) above: ##STR35## wherein alkylene, R_(o) and pare as defined with formula (I) above; the dotted line in formula (xii')indicates the presence of a double bond in either the 4 or 5 position ofthe dihydropyridine ring; the dotted line in formula (xiii') indicatesthe presence of a double bond in either the 2 or 3 position of thedihydroquinoline ring; is the skeleton of a sugar molecule; n^(iv) is apositive integer equal to the total number of --OH functions in thesugar molecule from which said skeleton is derived; n^(v) is a positiveinteger one less than the total number of --OH functions in the sugarmolecule from which said skeleton is derived; each A in each ofstructures (xii'), (xiii'), (xiv') and (xiv") can independently behydroxy or D', D' being the residue of a centrally acting drugcontaining one reactive carboxyl functional group, said residue beingcharacterized by the absence of a hydrogen atom from said carboxylfunctional group in said drug; and each R₄ in each of structures (x')and (xi') can independently be hydroxy, ##STR36## wherein alkylene,R_(o) and p are defined as with formula (I); the dotted line is definedas with structures (xii') and (xiii'); D' is defined as with structures(xii'), (xiii'), (xiv') and (xiv"); R₁ is C₁ -C₇ alkyl, C₁ -C₇ haloalkylor C₇ -C₁₀ aralkyl; and the depicted carbonyl groupings can be attachedat the 2, 3 or 4 position of the pyridinium or quinolinium ring or,except where otherwise specified, at the 1, 3 or 4 position of theisoquinolinium ring; with the proviso that at least one R₄ in each ofstructures (x') and (xi') is ##STR37## wherein alkylene, R_(o), p, R₁,the dotted lines and the position of the carbonyl-containing groupingsare defined as above; and with the further proviso that when more thanone of the R₄ radicals in a given compound are the aforesaidcarbonyl-containing groupings, then all such carbonyl-containinggroupings in said compound are identical.

(4') For Group (3) above: ##STR38## wherein alkylene, R_(o) and p are asdefined with formula (I); R is hydrogen, C₁ -C₇ alkyl, C₃ -C₈ cycloakyl,C₁ -C₇ haloalkyl, furyl, phenyl, or phenyl substituted by one or morehalo, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl, loweralkanoyloxy, lower haloalkyl, mono(lower alkyl)carbamoyl, di(loweralkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or loweralkylsulfonyl; the dotted line in formulas (k'), (l') and (m') indicatesthe presence of a double bond in either the 4 or 5 position of thedihydropyridine ring; the dotted line in formulas (n'), (o') and (p')indicates the presence of a double bond in either the 2 or 3 position ofthe dihydroquinoline ring; R₁ is C₁ -C₇ alkyl, C₁ -C₇ haloalkyl or C₇-C₁₀ aralkyl; R₃ is C₁ to C₃ alkylene, X is --CONR'R", wherein R' andR", which can be the same or different, are each H or C₁ -C₇ alkyl, or Xis --CH--NOR"' wherein R"' is H or C₁ -C₇ alkyl; the carbonyl-containinggroupings in formulas (k') and (m') an d the X substituent in formula(1') can each be attached at the 2, 3 or 4 position of thedihydropyridine ring; the carbonyl-containing groupings in formulas (n')and (p') and the X substituent in formula (o') can each be attached atthe 2, 3 or 4 position of the dihydroquinoline ring; and thecarbonyl-containing groupings in formulas (q') and (s') and the Xsubstituent in formulas (r') can each be attached at the 1, 3 or 4position of the dihydroisoquinoline ring.

The presently preferred dihydropyridine⃡pyridinium salt redox carriermoieties of this invention are those wherein alkylene is --CH₂ --; p is1; R_(o) is H, --CH₃, --CH(CH₃)₂, --CH₂ --CH(CH₃)₂, ##STR39## or --CH₂CH₂ --CONH₂ ; R₁, when present, is --CH₃ ; R₃, when present, is --CH₂CH₂ --; X when present, is --CONH₂ ; the depicted carbonyl -containinggroupings in formulas (a) and (c) and the X substituent in formula (b)are attached at the 3-position; the depicted carbonyl-containinggroupings in formulas (d) and (f) and the X substituent in formula (e)are attached at the 3-position; the depicted carbonyl-containinggroupings formulas (g) and (j) and the X substituent in formula (h) areattached at the 4-position; Z', when present, is C₂ or C₃ straight orbranched alkylene; Q, when present, is --NH--; the X substituent informulas (ii) and (v) and the depicted carbonyl-containing groupings informulas (i), (iii), (iv) and (vi) are attached at the 3-position; the Xsubstituent in formula (viii) and the depicted carbonyl-containinggroupings is formulas (vii) and (ix) are attached at the 4-position; andthe depicted carbonyl-containing groupings encompassed by formulas (x),(xi), (xii), (xiii) and (xiv) are in the 3-position of the pyridinium orquinolinium ring and in the 4-position of the isoquinolinium ring; allR'₄ 's in structures (x) and (xi) are --OH except for the one R₄ in eachstructure which must be the carrier moiety; all A's in structures (xii),(xiii) and (xiv) are --OH; is skeleton of a glucose molecule; R informulas the (k), (l) and (m) is hydrogen, methyl or CCl₃ ; and thedepicted carbonyl-containing groupings in formulas (k) through (s) arein the 3-position of the pyridinium or quinolinium ring and in the4-position of the isoquinolinium ring; and the corresponding dihydromoieties.

Especially preferred dihydropyridine⃡pyridinium salt redox carriermoieties are the quaternaries of Group (1), structures (a), (b), (d),(e), (g) and (h); those of Group (2), structures (i), (ii), (iv), (v),(vii), (viii), (x) and (xii); and those of Group 3, structures (k), (l),(n), (o), (q) and (r); and the corresponding dihydro forms, mostespecially when they contain the preferred structural variablesidentified in the preceding paragraph.

The following synthetic schemes illustrate various approaches to thepreparation of the compounds of this invention. ##STR40##

Similar schemes can be shown for the preparation of the other compoundsof the invention. The acylation steps which introduce the hydroxylprotecting groups in Scheme 1, 2 and 4, for example, are only neededwhen there are hydroxyl groups which it is desired to protect. Moreover,carbonate rather than acyl protecting groups could be introducedinstead, as already discussed hereinabove. Also, as shown in Schemes 2and 3, the order of steps may be altered; quaternization, followed byreduction, need not always constitute the final two steps but may becarried out earlier in the reaction sequence. Yet other reactionschemes, reactants, solvents, reaction conditions, etc. (e.g. using ananhydride rather than an acyl halide for the acylation step, orpreparing a different acyl derivative, e.g. the acetyl rather than thepivalyl derivative, or using a different amino acid or nicotinoylderivative thereof in place of glycine or nicotinuric acid,respectively) will be readily apparent to those skilled in the art.Also, insofar as concerns the quaternary compounds, when an aniondifferent from that obtained is desired, the anion in the quaternarysalt may be subjected to anion exchange via an anion exchange resin or,more conveniently, by use of the method of Kaminski et al, Tetrahedron,Vol. 34, pp. 2857-2859 (1978). According to the Kaminski et al method, amethanolic solution of an HY acid will react with a quaternary ammoniumhalide to produce the methyl halide and the corresponding quaternary.Ysalt. Moreover, the manner in which the ultimate compound is preparedshould be tailored to the presence of any other reactive groups in themolecule. For example, when the parent drug contains an --OH or --NH₂group to be derivatized as well as one or more carboxy functions, suchcarboxy functions will typically be esterified, e.g. converted to thecorresponding ethyl ester, or otherwise suitably protected, usuallyprior to formation of the quaternary compound. Thus, a wide variety ofsynthetic approaches can be utilized, depending on the desired structureof the final product. And compounds containing more than one category ofreactive functional groups may be derivatized in a variety of ways; forexample, a compound containing reactive hydroxyl and carboxyl groups mayhave the hydroxyl group(s) protected and the carboxyl group(s) linked tothe carrier, or the hydroxyl(s) may be linked to the carrier and thecarboxyl(s) protected.

Various illustrative synthetic schemes as applied to specific compoundsof the invention are set forth below in the section entitled"Illustrative Synthetic Methods". While the sequence of reaction stepscan be varied in many cases, in general the final step (except in thecase of optional salt formation or possibly in the case ofradiolabeling) will be reduction of a quaternary compound of formula(II) to the corresponding dihydro compound of formula (I). The reductionis usually conducted at a temperature from about -10° C. to roomtemperature, for a period of time from about 10 minutes to 2 hours,conveniently at atmospheric pressure. Typically, a large excess ofreducing agent is employed, e.g. a 1:5 molar ratio of reducing agent tostarting compound of formula (II). The process is conducted in thepresence of a suitable reducing agent, preferably an alkali metaldithionite such as sodium dithionite or an alkali metal borohydride suchas sodium borohydride or lithium aluminum borohydride, in a suitablesolvent. Sodium dithionite reduction is conveniently carried out in anaqueous solution; the dihydro product of formula (I) is usuallyinsoluble in water and thus can be readily separated from the reactionmedium. In the case of sodium borohydride reduction, an organic reactionmedium is employed, e.g. a lower alkanol such as methanol, an aqueousalkanol or other protic solvent.

In a presently preferred embodiment of the present invention, thecentrally acting drug of which D is the residue is dopamine or L-DOPA ora protected counterpart thereof, and the instant redox system is thusdesigned to elicit a sustained and brain-specific dopaminergic (e.g.anti-Parkinsonism or anti-hyperprolactinemia) response in the animal towhich the formula (I) derivative is administer ed. In analogous fashion,the instant redox carrier system I⃡II in which D is the residue of anyother centrally acting drug as defined herein is designed to elicit thekind of pharmacological response which would be obtained by delivery ofthe drug itself to the brain, i.e. when the centrally acting parent drugis an antitumor/anticancer agent, the instant redox system is employedto elicit an antitumor/anticancer response; when the parent drug is asympathetic stimulant, the instant redox system is used to elicit asympathetic stimulant or amphetamine-like response; when the parent drugis an anticonvulsant compound, the instant redox system is used toelicit an anticonvulsant response; when the parent drug is atranquilizer, the instant system is used to elicit a tranquilizingresponse; when the parent drug is an antidepressant, the instant systemis used to elicit an antidepressant response; and so forth.

Suitable nontoxic pharmaceutically acceptable carriers for use with thetopic compounds of formula (I), e.g. those less toxic than the targetdrug species themselves, will be apparent to those skilled in this art.Compare, for example, Remington's Pharmaceutical Sciences, 4th Edition(1970). Obviously, the choice of suitable carriers will depend upon theexact nature of the particular dosage form selected, as well as upon theidentity of the compound to be administered. The therapeutic dosagerange for administration of a compound according to this invention willgenerally be the same as, or less than, those which wouldcharacteristically be used in this art for administration of the parentdrug itself. Naturally, such therapeutic dosage ranges will vary withthe size of the patient, the condition for which the compound isadministered, the particular dosage form employed, route ofadministration and the like. The quantity of given dosage form needed todeliver the desired dose will of course depend upon the concentration ofthe compound of formula (I) in any given pharmaceuticalcomposition/dosage form thereof. Obviously, in the case of diagnosticagents, the dosage of formula (I) compound used will be a quantitysufficient to deliver to the target body area an amount of radioisotope,stable isotope or the like which can be effectively detected byradio-imaging or other detection means. The amount of radioisotope,stable isotope or the like present in the dosage form will be within orbelow the ranges conventionally used for diagnostic purposes.

The ability of the topic compounds to cross the BBB and to be "lockedinto" the brain allows administration in a site-specific manner. Acombination of the present dihydropyridine⃡pyridinium salt redox carriersystem with a sustained release system will further enhance thissite-specificity. Thus, a preferred embodiment of the inventioncomprises formulating the compound of formula (I) or its salt utilizinga sustained release carrier system and/or route of administrationcapable of slowly releasing the chemical, e.g. sustained release tabletsand capsules for oral administration; subcutaneous injection, orimplantation of drugs in solid pellet form (for example, distributed ina biodegradable polymer); intramuscular injection of the compound insolution in oil or suspended in a repository vehicle; a transdermaldelivery device or form such as an ointment to be applied locally to thedesired site (when the drug is susceptible of delivery through theskin), slow intravenous infusion and the like. The rate of release ofcompound from the sustained release system should be comparable to therate of in vivo oxidation of the dihydro form of the redox system inorder to achieve the greatest degree of enhancement of specificity.

In applicant's copending application Ser. No. 632,314, filed Jul. 19,1984 (itself a continuation-in-part of the earlier Ser. No. 379,316, nowU.S. Pat. No. 4,479,932; Ser. No. 461,543, abandoned in favor of Ser.No. 733,463, filed May 13, 1985, now U.S. Pat. No. 4,727,079; Ser. No.475,493 now U.S. Pat. No. 4,622,218; and Ser. No. 516,382 now U.S. Pat.No. 4,540,564), Ser. No. 632,314 being abandoned in favor of Ser. No.879,120, filed Mar. 19, 1986, in turn abandoned in favor of Ser. No.088,523, filed Aug. 21, 1987, now U.S. Pat. No. 4,963,688), the conceptof applicant's redox carrier system was expanded to provide novelcarrier-containing chelating agents, precursors thereto andradiopharmaceuticals derived therefrom, utilizing thedihydropyridine⃡pyridinium salt type carriers disclosed in the fourearlier applications. The teachings of Ser. No. 632,314, which isincorporated by reference herein in its entirety and relied upon, can bereadily combined with the teachings of the present application to expandthe classes of chelating agents, precursors and radiopharmaceuticalsdefined therein to specifically include dihydropyridine⃡pyrdinium saltredox carriers comprising a bivalent radical of the formula ##STR41## asdefined herein.

ILLUSTRATIVE SYNTHETIC METHODS I. Methods for Derivatizing --NH₂ or--NH-- Functions in Drugs

Method A

The drug is reacted with nicotinuric acid chloride, with nicotinuricacid anhydride, or with nicotinuric acid in the presence of a suitablecoupling agent such as dicyclohexylcarbodiimide, in an appropriateorganic solvent, to afford the corresponding glycylnicotinamide, ornicotinuramide. The nicotinuramide is then quaternized, typically bytreatment with methyl iodide in a suitable organic solvent, to affordthe quaternary derivative of formula (II), which is then reduced bytreatment with sodium dithionite or sodium borohydride as generallydescribed hereinabove to afford the desired compound of formula (I). Therepresentative drugs depicted below may be derivatized in this manner tothe corresponding compounds of formulas (II) and (I). Bupropion,difluamine, propranolol, ethyl β-carboline-3-carboxylate, prizidilol,pseudoephedrine, 5-amidino-2-(5-amidino-2-benzofuranyl)indole,4',6-diimidazolino-2-phenylbenzo(b)thiophene,2-guanidino-4,5-di-n-propyloxazole, 2-guanidino-4,5-diphenyloxazole,glucosamine, 6-amino-6-deoxy-D-glucose and6[[(hydroxyimino)phenyl]methyl]-1-[(methylethyl)sulfonyl-1H-benzimidazol-2-aminemay be similarly derivatized.

Alternatively, glycine may be first reacted with a reagent capable ofintroducing an amino protecting group such as benzyloxycarbonyl ort-butoxycarbonyl (e.g. as in Scheme 1 or 2 hereinabove) and theN-protected glycine then reacted with the drug in the presence of acoupling agent such as dicyclohexylcarbodiimide, followed by removal ofthe N-protecting group, followed by reaction with nicotinoyl chloride ornicotinic anhydride, or with nicotinic acid in the presence ofdicyclohexylcarbodiimide or other suitable coupling agent, to afford thenicotinuramide. The nicotinuramide may then be quaternized and thequatenary reduced as described in the preceding paragraph.

The procedure of the second paragraph of this method may be repeatedusing picolinic acid or its acid chloride or anhydride, or isonicotinicacid or its acid chloride or anhydride, in place of nicotinic acid orits acid chloride or anhydride, respectively, to convert drugs such asthose specifically mentioned for derivatizing by this method to thecorresponding glycyl picolinamides and glycyl isonicotinamides and thento the corresponding compounds of formula (II) and (I). The procedure ofthe first paragraph of this method may be similarly adapted. Moreover,any of these procedures may be repeated, substituting a different aminoacid or nicotinic acid derivative thereof for the glycine or nicotinuricacid used above, e.g. replacing glycine with alanine, valine, leucine,phenylalanine, isoleucine, methionine, asparagine or glutamine.

Alternatively, the drug may be reacted with an activated ester ofnicotinuric acid or the like, e.g. a sucinimidyl ester such as ##STR42##and the product quaternized and then reduced as described in the firstparagraph of this method to afford the identical products. As yetanother alternative, the activated ester, e.g. the succinimidyl esterdepicted above, may be quaternized (e.g. by treatment with methyliodide) and the quaternized activated ester then reacted with the drug.The quaternary compound of formula (II) thus obtained may then bereduced as described in the first paragraph of this method to give thecorresponding compound of formula (I).

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR43##      ##STR44##      ##STR45##      ##STR46##      ##STR47##      ##STR48##      ##STR49##      ##STR50##      ##STR51##      ##STR52##      ##STR53##      ##STR54##      ##STR55##      ##STR56##      ##STR57##      ##STR58##      ##STR59##      ##STR60##      ##STR61##      ##STR62##      ##STR63##      ##STR64##      ##STR65##      ##STR66##      ##STR67##      ##STR68##      ##STR69##      ##STR70##      ##STR71##      ##STR72##      ##STR73##      ##STR74##      ##STR75##      ##STR76##      ##STR77##      ##STR78##      ##STR79##      ##STR80##      ##STR81##      ##STR82##      ##STR83##      ##STR84##      ##STR85##      ##STR86##      ##STR87##      ##STR88##      ##STR89##      ##STR90##      ##STR91##      ##STR92##      ##STR93##      ##STR94##      ##STR95##      ##STR96##      ##STR97##      ##STR98##      ##STR99##      ##STR100##      ##STR101##      ##STR102##      ##STR103##      ##STR104##      ##STR105##      ##STR106##      ##STR107##      ##STR108##      ##STR109##      ##STR110##      ##STR111##      ##STR112##      ##STR113##      ##STR114##      ##STR115##      ##STR116##      ##STR117##      ##STR118##      ##STR119##      ##STR120##      ##STR121##      ##STR122##      ##STR123##      ##STR124##      ##STR125##      ##STR126##      ##STR127##      ##STR128##      ##STR129##      ##STR130##      ##STR131##      ##STR132##      ##STR133##      ##STR134##      ##STR135##      ##STR136##      ##STR137##      ##STR138##      ##STR139##      ##STR140##      ##STR141##      ##STR142##      ##STR143##      ##STR144##      ##STR145##      ##STR146##      ##STR147##      ##STR148##      ##STR149##      ##STR150##      ##STR151##      ##STR152##      ##STR153##      ##STR154##      ##STR155##      ##STR156##      ##STR157##      ##STR158##      ##STR159##      ##STR160##      ##STR161##      ##STR162##      ##STR163##      ##STR164##      ##STR165##      ##STR166##      ##STR167##      ##STR168##      ##STR169##      ##STR170##      ##STR171##      ##STR172##      ##STR173##      ##STR174##      ##STR175##      ##STR176##      ##STR177##      ##STR178##      ##STR179##      ##STR180##      ##STR181##      ##STR182##      ##STR183##      ##STR184##      ##STR185##      ##STR186##      ##STR187##      ##STR188##      ##STR189##      ##STR190##      ##STR191##      ##STR192##      ##STR193##      ##STR194##      ##STR195##      ##STR196##      ##STR197##      ##STR198##

Method B

This is a variation of Method A used when the drug contains at least one--COOH function which is to be protected.

The drug is first converted to the corresponding t-butyl ester byconventional esterification techniques. That ester is then used as thestarting material and Method A is repeated.

Obviously, other esters may be similarly prepared in the first step byuse of other esterifying agents.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I).Ceforanide, furosemide and acivicin may be similarly derivatized.

The glycyl picolinamide and glycyl isonicotinamide quaternary anddihydro derivatives of the drugs specifically mentioned for derivatizingaccording to this method may be similarly prepared, as may derivativesof other amino acids. See Method A, last paragraph.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR199##      ##STR200##      ##STR201##      ##STR202##      ##STR203##      ##STR204##      ##STR205##      ##STR206##      ##STR207##      ##STR208##      ##STR209##      ##STR210##      ##STR211##      ##STR212##      ##STR213##      ##STR214##      ##STR215##      ##STR216##      ##STR217##      ##STR218##      ##STR219##      ##STR220##      ##STR221##      ##STR222##      ##STR223##      ##STR224##      ##STR225##

Method C

This is a variation of Method A used when the drug contains one or moreOH functions which are to be protected.

The drug is first reacted with excess trimethylacetyl chloride toconvert the hydroxy group(s) to pivalyloxy group(s). (This process isgenerally conducted in the presence of a base; however, strongly acidconditions are used when an amine function is present.) That protectedderivative is then used as the starting material and subjected to MethodA. Alternatively, the first two steps may be reversed, i.e. the drug maybe first converted to the nicotinuramide, which may then be reacted withtrimethylacetyl chloride to form the protected nicotinuramide.

Various other hydroxy protecting groups may be introduced in similarfashion.

The representative drugs depicted be low may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I). Thecorresponding glycyl picolinamide and glycyl isonicotin amide quaternaryand dihydro derivatives may be similarly prepared, as may derivatives ofamino acids other than glycine. See Method A, last paragraph. Moreover,drugs such as norepiniphrine, epinephrine, phenylephrine, atenolol,metoprolol, pentostatin (2'-deoxycoformycin), glucosamine,6-amino-6-deoxy-D-glucose and pseudoephedrine may be similarlyderivatized.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR226##      ##STR227##      ##STR228##      ##STR229##      ##STR230##      ##STR231##      ##STR232##      ##STR233##      ##STR234##      ##STR235##      ##STR236##      ##STR237##

Method D

This variation of Method A can be used when the drug contains one ormore OH and COOH functions which are to be protected. The protectinggroups, for example, the t-butyl ester and pivalyloxy groups, areintroduced as described in Methods B and C, in the sequence consideredmost convenient. (Obviously, other protecting groups can be introducedinstead. The amine function is derivatized according to Method A.

The representative drugs listed below may be derivatized in this mannerto the corresponding compounds of formulas (II) and (I). Thecorresponding glycyl picolinamide and glycyl isonicotinamide quaternaryand dihydro derivatives may be similarly prepared, as may derivatives ofamino acids other than glycine. See Method A, last paragraph.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR238##      ##STR239##      ##STR240##      ##STR241##      ##STR242##      ##STR243##

Method E

This method is of particular use when the --NH-- function is part of anamide or imide or a very low pKa primary or secondary amine.

The drug is first reacted with an aldehyde [e.g. formaldehyde,benzaldehyde, acetaldehyde or chloral (Cl₃ CCHO)]; for example, in thecase of formaldehyde, one converts the --NH-- function to a ##STR244##function and thus forms a suitable bridging group. The resultantcompound is then reacted with nicotinuric acid in the presence of asuitable dehydrating agent, or with nicotinuric acid chloride ornicotinuric acid anhydride, to form the corresponding nicotinuric acidester of the partial formula ##STR245## The resultant intermediate isthen quaternized and reduced as in Method A. The alternative processutilizing an activated ester or quaternary derivative thereof which isdescribed in Method A may be utilized here as well.

The representative starting drugs depicted below may be derivatized inthis manner to the corresponding compounds of formulas (II) and (I).Drugs such as minocycline, doxycycline, oxytetracycline, tetracycline,methacycline, atenolol, sulfadiazine, cyclophosphamide, dactinomycin,mitomycin, 3-deazaguanine, progabide and 6-mercaptopurine may besimilarly derivatized.

Alternatively, the steps subsequent to formation of the ##STR246##function may be replaced with steps analogous to those detailed in thesecond paragraph of Method A.

The procedure of the preceding paragraph may be repeated using picolinicacid or its acid chloride or anhydride, or isonicotinic acid or its acidchloride or anhydride, in place of nitotinic acid or its acid chlorideor anhydride, respectively (as called for in the second paragraph ofMethod A), to convert drugs such as those specifically mentioned forderivatizing according to this Method to the corresponding glycylpicolinic acid esters and glycyl isonicotinic acid esters and then tothe corresponding compounds of formulas (II) and (I). Derivatives ofamino acids other than glycine may be similarly prepared. See Method A,last paragraph.

As yet another alternative, the intermediate compound containing the##STR247## group or the like may be reacted with thionyl chloride toafford the corresponding compound containing a ##STR248## or similargroup. That derivative may then be reacted with a metallic salt(especially a silver or thallous salt) of nicotinuric acid or the like(formed, e.g. by reacting nicotinuric acid or the like with fresh silverhydroxide or oxide or with thallous ethoxide). The resultant nicotinuricacid ester of the partial formula ##STR249## or like derivative is thenquaternized and subsequently reduced as in Method A.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR250##      ##STR251##      ##STR252##      ##STR253##      ##STR254##      ##STR255##      ##STR256##      ##STR257##      ##STR258##      ##STR259##      ##STR260##      ##STR261##      ##STR262##      ##STR263##      ##STR264##      ##STR265##      ##STR266##      ##STR267##      ##STR268##      ##STR269##      ##STR270##      ##STR271##      ##STR272##      ##STR273##      ##STR274##      ##STR275##      ##STR276##      ##STR277##      ##STR278##      ##STR279##      ##STR280##      ##STR281##      ##STR282##      ##STR283##      ##STR284##      ##STR285##      ##STR286##      ##STR287##      ##STR288##      ##STR289##      ##STR290##      ##STR291##      ##STR292##      ##STR293##      ##STR294##      ##STR295##      ##STR296##      ##STR297##      ##STR298##      ##STR299##      ##STR300##      ##STR301##      ##STR302##      ##STR303##      ##STR304##      ##STR305##      ##STR306##      ##STR307##      ##STR308##      ##STR309##      ##STR310##      ##STR311##      ##STR312##      ##STR313##      ##STR314##      ##STR315##      ##STR316##      ##STR317##      ##STR318##      ##STR319##      ##STR320##      ##STR321##      ##STR322##      ##STR323##      ##STR324##      ##STR325##      ##STR326##      ##STR327##      ##STR328##      ##STR329##      ##STR330##      ##STR331##      ##STR332##      ##STR333##      ##STR334##      ##STR335##      ##STR336##      ##STR337##      ##STR338##      ##STR339##

Method F

This method is a variation of Method E which can be used when the --NH--function is part of an amide or imide or low pKa primary or secondaryamine and the drug contains one or more --COOH functions which is/are tobe protected. Typically, the carboxyl group or groups is/are firstconverted to the corresponding pivaloyloxymethyl ester by knownesterification techniques. Obviously, other esters may be similarlyprepared. The ester is then used as the starting material and Method Eis repeated.

The representative starting drugs depicted below may be derivatized inthis manner to the corresponding compounds of formulas (II) and (I).Drugs such as carbenicillin, phenoxymethylpenicillin, methicillin,nafcillin, ticarcillin, dicloxacillin, cefazolin, cefoxitin, moxalactam,aminopterin, furosemide, and 5-methyltetrahydrohomofolic acid may besimilarly derivatized.

The alternative procedures described in Method E, last paragraph, may beused in Method F also.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR340##      ##STR341##      ##STR342##      ##STR343##      ##STR344##      methotrexate      ##STR345##      ##STR346##      ##STR347##      ##STR348##      ##STR349##      ##STR350##      ##STR351##      ##STR352##      ##STR353##

Method G

This is a variation of Method E used when the drug also contains one ormore hydroxy functions which are to be protected. Typically, the drug isfirst reacted with excess trimethylacetyl chloride to convert thehydroxy group(s) to pivalyloxy group(s). That protected derivative isthen used as the starting material and subjected to Method E.

Other hydroxy protecting groups may be introduced in similar fashion.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I).

The alternative procedures described in Method E, last paragraph, may beused in Method G also.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR354##      ##STR355##      ##STR356##      ##STR357##      ##STR358##      ##STR359##

Method H

The procedure of the second paragraph of Method A is followed, exceptthat removal of the N-protecting group is followed by reaction with3-quinolinecarboxylic acid or its acid chloride or anhydride instead ofnicotinic acid or its acid chloride or anhydride.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I), as maythe remaining drugs mentioned with Method A.

The procedure of the first paragraph of Method A may be similarlyadapted to the production of the 3-quinolinecarboxylic acid derivatives.Moreover, Method H may be combined with Methods B, C, D, E, F or G toafford the corresponding 3 -quinolinecarboxylic acid derivatives of thedrugs mentioned with those methods.

The procedure of the first paragraph of this method may be repeatedusing 4-isoquinolinecarboxylic acid or its acid chloride or anhydride toconvert drugs such as those mentioned with Methods A, B, C, D, E, F or Gto the corresponding 4-isoquinolinecarboxylic acid derivatives.

The procedure of the first or fourth paragraph of this method may berepeated, substituting a different amino acid, e.g. alanine, valine,leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine,for the glycine used in the first step. (See Method A, secondparagraph).

The general procedures described above may be utilized to provide the1,2-dihydro derivatives as well as the depicted 1,4-dihydros.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR360##      ##STR361##      ##STR362##      ##STR363##      ##STR364##      ##STR365##      ##STR366##      ##STR367##      ##STR368##      ##STR369##      ##STR370##      ##STR371##      ##STR372##      ##STR373##      ##STR374##      ##STR375##      ##STR376##      ##STR377##      ##STR378##      ##STR379##      ##STR380##      ##STR381##      ##STR382##      ##STR383##      ##STR384##      ##STR385##      ##STR386##

Method I

The procedure of the second paragraph of Method is followed, except thata reactant of the formula ##STR387## is used place of nicotinic acid.(That starting material may be prepared by reacting nicotinic anhydride,nicotinoyl chloride or nicotinic acid with glycolic acid.)

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I), as maythe remaining drugs listed with Method A.

Similarly, Method I may be combined with Methods B, C or D to afford thecorresponding derivatives, e.g. of the drugs mentioned with thosemethods.

The foregoing procedure can be repeated using picolinic acid or its acidchloride or anhydride, or isonicotinic acid or its acid chloride oranhydride, in place of nicotinic acid or its acid chloride or anhydride,respectively, in the preparation of the reactant depicted above. Thisvariation affords a reactant of the formula ##STR388## which can then beused in place of nicotinic acid to prepare derivatives of drugs such asthose mentioned with Methods A, B, C or D.

The procedure of the first or fourth paragraph of this method may berepeated, substituting a different amino acid, e.g. alanine, valine,leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine,for the glycine used in the first step. (See Method A, secondparagraph).

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR389##      ##STR390##      ##STR391##      ##STR392##      ##STR393##      ##STR394##      ##STR395##      ##STR396##      ##STR397##      ##STR398##      ##STR399##      ##STR400##      ##STR401##      ##STR402##      ##STR403##      ##STR404##      ##STR405##      ##STR406##

Method J

The procedure of the second paragraph of Method A is followed, exceptthat a reactant of the formula ##STR407## wherein n=1-3, preferably 2,is used in place of nicotinic acid. (That reactant may be prepared fromnicotinamide, e.g. when n=2, by reacting 3-iodopropionic acid withnicotinamide.) The quaternary salt of formula (II) thus obtained maythen be reduced as described in Method A.

The drugs depicted below may be derivatized in this manner to thecorresponding compounds of formulas (II) and (I), as may the remainingdrugs mentioned with Method A.

Similarly, Method j may be combined with Methods B, C or D to afford thecorresponding derivatives, e.g. of the drugs mentioned with thosemethods.

The procedure described above can be repeated using picolinamide orisonicotinamide in place of nicotinamide in the preparation of thereactant depicted above. This variation affords a reactant of theformula ##STR408## which can then be used in place of nicotinic acid inthe procedure of the first paragraph of this method, to afford thecorresponding derivatives, e.g. of the drugs mentioned with Methods A,B, C or D.

The procedure of the first or fourth paragraph of this method can berepeated, substituting a different amino acid, e.g. alanine, valine,leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine,for the glycine used in the first step. (See Method A, secondparagraph).

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR409##      ##STR410##      ##STR411##      ##STR412##      ##STR413##      ##STR414##      ##STR415##      ##STR416##      ##STR417##      ##STR418##      ##STR419##      ##STR420##

II. Methods for Derivatizing --OH and --SH Functions in Drugs

Method K

The drug is reacted with nicotinuric acid chloride, with nicotinuricacid anhydride, or with nicotinuric acid in the presence of a suitablecoupling agent such as dicyclohexyl carbodiimide, in an appropriateorganic solvent, to afford the corresponding glycylnicotinate, ornicotinurate. The nicotinurate is then quaternized and subsequentlyreduced as described above in Method A. When the drug contains more thanone reactive hydroxyl or thiol function, reaction conditions may bevaried so that more than one hydroxyl or thiol function will beconverted to nicotinurate groupings. The alternative process utilizingan activated ester or quaternary derivative thereof which is describedin Method A may be utilized here as well.

Alternatively, glycine may be first reacted with a reagent capable ofintroducing an amino protecting group such as benzyloxycarbonyl ort-butylcarbonyl (e.g. as in Scheme 1 or 2 hereinabove) and the N-protected glycine then reacted with the drug in the presence of acoupling agent such as dicyclohexylcarbodiimide, followed by removal ofthe N- protecting group, followed by reaction with nicotinoyl chlorideor nicotinic anhydride, or with nicotinic acid in the presence ofdicyclohexylcarbodiimide or other suitable coupling agent, to afford thenicotinurate. The nicotinurate may then be quaternized and thequaternary reduced as described in the preceding paragraph.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I). Estriol,lincomycin, apomorphine, meptazinol, cyclazocine, phenazocine, metopon,myfadol, naltrexone, alazocine, oxilorphan, nalmexone, thioguanine,levorphanol, benzestrol, diethylstilbestrol, pentostatin(2'-deoxycoformycin), tiazofurin, sangivamycin, 2 -deoxy-D-glucose,2-deoxy-2-fluoro-D-mannose andphenyl-6-chloro-6-deoxy-β-D-glucopyranoside may be similarlyderivatized.

The procedure of the second paragraph of this method may be repeatedusing picolinic acid or its acid chloride or anhydride, or isonicotinicacid or its acid chloride or anhydride, in place of nicotinic acid orits acid chloride or anhydride, respectively, to convert drugs such asthose specifically mentioned for derivatizing by this method to thecorresponding glycyl picolinic acid esters or glycyl isonicotinic acidesters and then to the corresponding compounds of formulas (II) and (I).The procedure of the first paragraph of this method may be similarlyadapted. Moreover, any of these procedures may be repeated, substitutinga different amino acid or nicotinic acid derivative thereof for theglycine or nicotinuric acid used above, e.g. replacing glycine withalanine, valine, leucine, phenylalanine, isoleucine, methionine,asparagine or glutamine.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR421##      ##STR422##      ##STR423##      ##STR424##      ##STR425##      ##STR426##      ##STR427##      ##STR428##      ##STR429##      ##STR430##      ##STR431##      ##STR432##      ##STR433##      ##STR434##      ##STR435##      ##STR436##      ##STR437##      ##STR438##      ##STR439##      ##STR440##      ##STR441##      ##STR442##      ##STR443##      ##STR444##      ##STR445##      ##STR446##      ##STR447##      ##STR448##      ##STR449##      ##STR450##      ##STR451##      ##STR452##      ##STR453##      ##STR454##      ##STR455##      ##STR456##      ##STR457##      ##STR458##      ##STR459##      ##STR460##      ##STR461##      ##STR462##      ##STR463##      ##STR464##      ##STR465##      ##STR466##      ##STR467##      ##STR468##      ##STR469##      ##STR470##      ##STR471##      ##STR472##      ##STR473##      ##STR474##      ##STR475##      ##STR476##      ##STR477##      ##STR478##      ##STR479##      ##STR480##      ##STR481##      ##STR482##      ##STR483##      ##STR484##      ##STR485##      ##STR486##      ##STR487##      ##STR488##      ##STR489##      ##STR490##      ##STR491##      ##STR492##      ##STR493##      ##STR494##      ##STR495##      ##STR496##      ##STR497##      ##STR498##      ##STR499##      ##STR500##      ##STR501##      ##STR502##      ##STR503##      ##STR504##      ##STR505##      ##STR506##      ##STR507##      ##STR508##      ##STR509##

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR510##      ##STR511##      ##STR512##      ##STR513##      ##STR514##      ##STR515##      ##STR516##      ##STR517##      ##STR518##      ##STR519##      ##STR520##      ##STR521##      ##STR522##      ##STR523##      ##STR524##      ##STR525##      ##STR526##      ##STR527##      ##STR528##      ##STR529##      ##STR530##      ##STR531##      ##STR532##      ##STR533##      ##STR534##      ##STR535##      ##STR536##      ##STR537##      ##STR538##      ##STR539##      ##STR540##      ##STR541##      ##STR542##      ##STR543##      ##STR544##      ##STR545##      ##STR546##      ##STR547##      ##STR548##      ##STR549##      ##STR550##      ##STR551##      ##STR552##      ##STR553##      ##STR554##      ##STR555##      ##STR556##      ##STR557##      ##STR558##      ##STR559##      ##STR560##      ##STR561##      ##STR562##      ##STR563##      ##STR564##      ##STR565##      ##STR566##      ##STR567##      ##STR568##      ##STR569##      ##STR570##      ##STR571##      ##STR572##      ##STR573##      ##STR574##      ##STR575##      ##STR576##      ##STR577##      ##STR578##      ##STR579##      ##STR580##      ##STR581##      ##STR582##      ##STR583##      ##STR584##      ##STR585##      ##STR586##      ##STR587##      ##STR588##      ##STR589##      ##STR590##      ##STR591##      ##STR592##      ##STR593##      ##STR594##      ##STR595##      ##STR596##      ##STR597##

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR598##      ##STR599##      ##STR600##      ##STR601##      ##STR602##      ##STR603##      ##STR604##      ##STR605##      ##STR606##      ##STR607##      ##STR608##      ##STR609##      ##STR610##      ##STR611##      ##STR612##      ##STR613##      ##STR614##      ##STR615##      ##STR616##      ##STR617##      ##STR618##      ##STR619##      ##STR620##      ##STR621##      ##STR622##      ##STR623##      ##STR624##      ##STR625##      ##STR626##      ##STR627##      ##STR628##      ##STR629##      ##STR630##      ##STR631##      ##STR632##      ##STR633##      ##STR634##      ##STR635##      ##STR636##      ##STR637##      ##STR638##      ##STR639##      ##STR640##      ##STR641##      ##STR642##      ##STR643##      ##STR644##      ##STR645##      ##STR646##      ##STR647##      ##STR648##      ##STR649##      ##STR650##      ##STR651##      ##STR652##      ##STR653##      ##STR654##      ##STR655##      ##STR656##      ##STR657##      ##STR658##      ##STR659##      ##STR660##      ##STR661##      ##STR662##      ##STR663##      ##STR664##      ##STR665##      ##STR666##      ##STR667##      ##STR668##      ##STR669##      ##STR670##      ##STR671##      ##STR672##      ##STR673##      ##STR674##      ##STR675##      ##STR676##      ##STR677##      ##STR678##      ##STR679##      ##STR680##      ##STR681##      ##STR682##      ##STR683##      ##STR684##      ##STR685##      ##STR686##      ##STR687##      ##STR688##      ##STR689##      ##STR690##      ##STR691##      ##STR692##      ##STR693##      ##STR694##      ##STR695##

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR696##      ##STR697##      ##STR698##      ##STR699##      ##STR700##      ##STR701##      ##STR702##      ##STR703##      ##STR704##      ##STR705##      ##STR706##      ##STR707##      ##STR708##      ##STR709##      ##STR710##      ##STR711##      ##STR712##      ##STR713##      ##STR714##      ##STR715##      ##STR716##      ##STR717##      ##STR718##      ##STR719##      ##STR720##      ##STR721##      ##STR722##      ##STR723##      ##STR724##      ##STR725##      ##STR726##      ##STR727##      ##STR728##      ##STR729##      ##STR730##      ##STR731##      ##STR732##      ##STR733##      ##STR734##      ##STR735##      ##STR736##      ##STR737##      ##STR738##      ##STR739##      ##STR740##      ##STR741##      ##STR742##      ##STR743##      ##STR744##      ##STR745##      ##STR746##      ##STR747##      ##STR748##      ##STR749##      ##STR750##      ##STR751##      ##STR752##      ##STR753##      ##STR754##      ##STR755##      ##STR756##      ##STR757##      ##STR758##      ##STR759##      ##STR760##      ##STR761##      ##STR762##      ##STR763##      ##STR764##      ##STR765##      ##STR766##      ##STR767##      ##STR768##      ##STR769##      ##STR770##      ##STR771##      ##STR772##      ##STR773##      ##STR774##      ##STR775##      ##STR776##      ##STR777##      ##STR778##      ##STR779##      ##STR780##      ##STR781##

Method K

This is an alternate process for derivatizing drugs containing secondaryor tertiary hydroxyl functional groups. According to this process, thedrug is reacted with chloral or other aldehyde capable of forming ahemiacetal therewith. In the case of chloral, this converts the --OHfunction(s) to ##STR782## groupings. The --OH function(s) of theresultant hemiacetal can then be derivatized by any of the methods forderivatizing --OH groups disclosed herein, e.g. by reaction withnicotinuric acid or its acid chloride or anhydride as described inMethod K.

This process is of particular value when the --OH group(s) in the drugis/are sterically hindered and/or when it is desired to alter the rateof release of the drug from that obtained when the carrier is hookeddirectly to the drug's hydroxy function(s).

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I). Otherdrugs containing secondary or tertiary --OH groups which are disclosedherein, e.g. in connection with Method K, may be similarly derivatized.This method is of special interest for derivatizing steroids containingsecondary or tertiary 17 β-hydroxy substituents, especially steroid sexhormones, and most especially such hormones bearing a bulky 17α-substituent such as a 17 α-ethynyl grouping.

      STARTING MATERIAL QUARTERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR783##      ##STR784##      ##STR785##      testosterone      ##STR786##      ##STR787##      ##STR788##      methyltestosterone      ##STR789##      ##STR790##      ##STR791##      norethandrolone      ##STR792##      ##STR793##      ##STR794##      norethindrone      ##STR795##      ##STR796##      ##STR797##      norethynodrel      ##STR798##      ##STR799##      ##STR800##      procyclidine

Method L

This variation of Method K can be used when the drug contains an aminogroup which needs to be protected. Generally, the amino group isprotected prior to any reaction of the hydroxyl function; typically, abenzyloxycarbonyl group is introduced in conventional manner to protectthe amino function and then the process described in the first, secondor fourth paragraph of Method K is followed. Removal of the protectinggroup, also in conventional manner, takes place after protection is nolonger needed, be it at the end of the synthetic pathway or earlier.Generally, the protecting group is removed before formation of theformula (II) quaternary. Occasionally, an amino protecting group will beutilized which need not be removed, for example, in the case oftrifluoroacetyldoxorubicin below.

The representative N- protected drugs depicted below may be derivatizedin this manner to the corresponding compounds of formulas (II) and (I).Norepinephrine, epinephrine, glucosamine, 6-amino-6-deoxy-D-glucose andpseudoephedrine may be similarly derivatized.

      STARTING MATERIAL QUARTERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR801##      ##STR802##      ##STR803##      N-benzyloxycarbonyldopamine      ##STR804##      ##STR805##      ##STR806##      N-benzyloxycarbonyltyramine      ##STR807##      ##STR808##      trifluoroacetyldoxorubicin      ##STR809##      ##STR810##      ##STR811##      ##STR812##      N-benzyloxycarbonyl-10-hydroxynortriptyline (E or Z isomer)      ##STR813##      ##STR814##      ##STR815##      N-benzyloxycarbonyl-2-hydroxydesipramine

Method M

This is a variation of Method K used when the drug contains a --COOHfunction which is to be protected.

The drug is first converted to the corresponding t-butyl ester byconventional esterification techniques. That ester is then used as thestarting material and the procedure of Method K, first, second or fourthparagraph, is repeated. The --COOH group may be similarly converted toother ester groups.

The representative drugs depicted be low may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I).Clorazepate and captopril may be similarly derivatized.

      STARTING MATERIAL QUARTERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR816##      ##STR817##      ##STR818##      sermetacin      ##STR819##      ##STR820##      ##STR821##      5-hydroxy-2-n-propylpentanoic acid      ##STR822##      ##STR823##      ##STR824##      4-hydroxy-2-n-propylpentanoic acid      ##STR825##      ##STR826##      ##STR827##      3-hydroxy-2-n-propylpentanoic acid      ##STR828##      ##STR829##      ##STR830##

Method N

The procedure of the second paragraph of Method K is followed, exceptthat a reactant of the formula ##STR831## wherein n=1-3, preferably 2(prepared as described in Method J), is used in place of nicotinic acid.The quaternary salt of formula (II) thus obtained may then be reduced asdescribed in Method A.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I), as maythe remaining drugs listed with Method K.

Similarly, Method N may be combined with Method L or M to afford thecorresponding derivatives, e.g. of the drugs listed with those methods.

A starting material of the formula set forth immediately above can alsobe substituted for nicotinic acid in the procedure of Method E, thirdparagraph, to afford the corresponding derivatives, e.g. of the drugslisted with that method. The drugs mentioned with Methods F and G may besimilarly derivatized.

Method N is of particular use in preparing derivatives of drugs in whichthe hydroxy function is hindered, e.g., biperiden, cycrimine,procyclidine and trihexyphenidyl.

Alternatively, Method N may follow Method K, second paragraph, exceptthat it employs a reactant of the formula ##STR832## (prepared asdescribed in Method J) in place of nicotinic acid, to afford derivativesof the drugs indicated with Method K. This alternative form of Method Nmay also be combined with Method L or M, to afford the correspondingderivatives of the drugs listed with Method L or M, respectively. Also,these alternative Method N starting materials may be substituted fornicotinic acid in Method E, third paragraph, to give the correspondingderivatives of the drugs listed with that method.

The procedures of this method may be repeated, substituting a differentamino acid, e.g. alanine, valine, leucine, phenylalanine, isoleucine,methionine, asparagine or glutamine, for the glycine used in the firststep. (See Method A, second paragraph).

      STARTING MATERIAL QUARTERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR833##      ##STR834##      ##STR835##      codeine      ##STR836##      ##STR837##      ##STR838##      nogestrel      ##STR839##      ##STR840##      piperacetazine      ##STR841##      ##STR842##      ##STR843##      ##STR844##      oxazepam      ##STR845##      ##STR846##      testosterone      ##STR847##      ##STR848##      ##STR849##      estrodiol      ##STR850##      ##STR851##      ##STR852##      ##STR853##      biperiden      ##STR854##      ##STR855##      ##STR856##      cycrimine      ##STR857##      ##STR858##      ##STR859##      procyclidine      ##STR860##      ##STR861##      ##STR862##      trihexyphenidyl

Method O

The procedure of Method K, second paragraph, is followed, except thatremoval of the N- protecting group is followed by reaction with3-quinolinecarboxylic acid or its acid chloride or anhydride instead ofnicotinic acid or its acid chloride or anhydride.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I), as maythe remaining drugs listed with Method K.

The procedure of the first paragraph of Method K may be similarlyadapted to the production of the 3-quinolinecarboxylic acid derivatives.Moreover, Method O may be combined with Method L or M to afford thecorresponding derivatives, e.g. of the drugs listed with those methods.

The procedure of Method O may be repeated using 4-isoquinolinecarboxylicacid or its acid chloride or anhydride in place of 3-quinolinecarboxylicacid or its acid chloride or anhydride, to afford the correspondingderivatives of drugs such as those indicated with Methods K, L and M.

3-Quinolinecarboxylic acid or its acid chloride or anhydride or4-isoquinolinecarboxylic acid or its acid chloride or anhydride can alsobe substituted for nicotinic acid or its acid chloride in Method E,fourth paragraph, to afford the corresponding derivatives, e.g. of thedrugs listed with that method.

The general procedures described above may be utilized to provide the1,2-dihydro derivatives as well as the depicted 1,4-dihydros.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR863##      ##STR864##      ##STR865##      ##STR866##      ##STR867##      ##STR868##      ##STR869##      ##STR870##      ##STR871##      ##STR872##      ##STR873##      ##STR874##      ##STR875##      ##STR876##      ##STR877##      ##STR878##      ##STR879##      ##STR880##      ##STR881##      ##STR882##      ##STR883##      ##STR884##      ##STR885##      ##STR886##      ##STR887##      ##STR888##      ##STR889##      ##STR890##      ##STR891##      ##STR892##      ##STR893##      ##STR894##      ##STR895##      ##STR896##      ##STR897##      ##STR898##      ##STR899##

Method P

The procedure of the second paragraph of Method K is followed, exceptthat a reactant of the formula ##STR900## is used in place of nicotinicacid.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I), as maythe remaining drugs listed with Method K.

Similarly, Method P may be combined with Methods L and M to afford thecorresponding derivatives, e.g. of the drugs listed with those methods.

A starting material of the formula set forth immediately above can alsobe substituted for nicotinic acid in Method E, paragraph 4, to affordthe corresponding derivatives, e.g. of the drugs listed with thatmethod.

Alternatively, Method P may follow Method K, second paragraph, exceptthat it employs a reactant of the formula ##STR901## (prepared asdescribed in Method I), to afford derivatives of the drugs indicatedwith Method K. This alternative form of Method P may also be combinedwith Method L or M, to afford the corresponding derivatives of the drugslisted with Method L or M. Also, these alternative Method P startingmaterials may be substituted for nicotinic acid in Method E, fourthparagraph, to give the corresponding derivatives of the drugs listedwith that method.

The procedure of the first or fifth paragraph of this method may berepeated, substituting a different amino acid, e.g. alanine, valine,leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine,for the glycine used in the first step. (See Method A, secondparagraph).

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR902##      ##STR903##      ##STR904##      ##STR905##      ##STR906##      ##STR907##      ##STR908##      ##STR909##      ##STR910##      ##STR911##      ##STR912##      ##STR913##      ##STR914##      ##STR915##      ##STR916##      ##STR917##      ##STR918##      ##STR919##

III. Methods for Derivatizing --COOH Functions in Drugs

Method Q

Nicotinuric acid (N-nicotinoylglycine) or an activated ester thereof isreacted with an aminoalkanol

    H.sub.2 N--Z'--OH

wherein Z' is C₁ -C₈ straight or branched alkylene, e.g. 2-aminoethanol,to afford the corresponding intermediate alcohol, e.g. in the case of2-aminoethanol, intermediate of the formula ##STR920## That alcohol isthen reacted with a drug containing one or more --COOH functions, in thepresence of a suitable coupling agent such as dicyclohexylcarbodiimide.The compound thus obtained is then quaternized and subsequently reducedas described above in Method A.

Nicotinuric acid is commercially available. However, it and analogousstarting materials can be readily prepared by reacting the selectedamino acid with the acid chloride of nicotinic acid, of picolinic acid,of isonicotinic acid, of 3-quinolinecarboxylic acid, of4-isoquinolinecarboxylic acid or the like to afford the desiredN-substituted amino acid, which can then be reacted with an aminoalkanolas described above.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I). Drugssuch as methicillin, ticarcillin, oxacillin, dicloxacillin, glyoxylicacid sulfonyl hydrazone, 5-methyltetrahydrohomofolic acid,phenoxymethylpenicillin, fenbufen, fenoprofen, indoprofen, ketoprofen,fluprofen, bucloxic acid, tolmetin, alclofenac, fenclozic acid,ibufenac, meclofenamic acid, flufenamic acid, flufenisal, clonixin,carprofen, etodolac, flutiazin, pirprofen, furosemide, cefoxitin andclorazepate may be similarly derivatized.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR921##      ##STR922##      ##STR923##      ##STR924##      ##STR925##      ##STR926##      ##STR927##      ##STR928##      ##STR929##      ##STR930##      ##STR931##      ##STR932##      ##STR933##      ##STR934##      ##STR935##      ##STR936##      ##STR937##      ##STR938##      ##STR939##      ##STR940##      ##STR941##      ##STR942##      ##STR943##      ##STR944##      ##STR945##      ##STR946##      ##STR947##      ##STR948##      ##STR949##      ##STR950##      ##STR951##      ##STR952##      ##STR953##      ##STR954##      ##STR955##      ##STR956##      ##STR957##      ##STR958##      ##STR959##      ##STR960##      ##STR961##      ##STR962##      ##STR963##      ##STR964##      ##STR965##      ##STR966##      ##STR967##      ##STR968##      ##STR969##      ##STR970##      ##STR971##      ##STR972##      ##STR973##      ##STR974##      ##STR975##      ##STR976##      ##STR977##      ##STR978##      ##STR979##      ##STR980##      ##STR981##      ##STR982##      ##STR983##      ##STR984##      ##STR985##      ##STR986##      ##STR987##      ##STR988##      ##STR989##      ##STR990##      ##STR991##      ##STR992##      ##STR993##      ##STR994##      ##STR995##      ##STR996##      ##STR997##      ##STR998##      ##STR999##      ##STR1000##      ##STR1001##      ##STR1002##      ##STR1003##      ##STR1004##      ##STR1005##      ##STR1006##      ##STR1007##      ##STR1008##      ##STR1009##      ##STR1010##      ##STR1011##      ##STR1012##      ##STR1013##      ##STR1014##      ##STR1015##      ##STR1016##

Method R

This is a variation of Method Q used when the drug contains one or more--OH or --SH functions which are to be protected.

The drug is first reacted with excess trimethylacetyl chloride toconvert the hydroxy group(s) to pivalyloxy group(s). (Various otherhydroxyl protecting groups may be introduced in similar fashion.) Theprotected drug is then reacted with the intermediate alcohol ##STR1017##in the presence of dicyclohexylcarbodiimide or other appropriate agentfor coupling the --COOH function of the drug to the hydroxy function ofthe depicted intermediate. (Other intermediate alcohols can be employed,e.g. as described in Method Q.) The resultant compound is thenquaternized and the quaternary subsequently reduced as in Method A.

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I). Drugssuch as clorazepate, 4-hydroxy-2-n-propylpentanoic acid,3-hydroxy-2-n-propylpentanoic acid and captopril may be similarlyderivatized.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR1018##      ##STR1019##      ##STR1020##      ##STR1021##      ##STR1022##      ##STR1023##      ##STR1024##      ##STR1025##      ##STR1026##      ##STR1027##      ##STR1028##      ##STR1029##      ##STR1030##      ##STR1031##      ##STR1032##      ##STR1033##      ##STR1034##      ##STR1035##      ##STR1036##      ##STR1037##

Method S

This is a variation of Method Q used when the drug contains one or moreamino functions which are to be protected. Generally, the amino group isprotected prior to any reaction of the carboxyl function; typically, abenzyloxycarbonyl group is introduced in conventional manner to protectthe amino function and then the N-protected drug is reacted with theintermediate alcohol as is Methods Q and R. Removal of the protectinggroup, in conventional fashion, takes place when protection is no longerneeded, generally before formation of the formula (II) quaternary andsubsequent reduction to the compound of formula (I).

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I).

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR1038##      ##STR1039##      ##STR1040##      ##STR1041##      ##STR1042##      ##STR1043##      ##STR1044##      ##STR1045##      ##STR1046##      ##STR1047##      ##STR1048##      ##STR1049##      ##STR1050##      ##STR1051##      ##STR1052##      ##STR1053##      ##STR1054##      ##STR1055##      ##STR1056##      ##STR1057##      ##STR1058##      ##STR1059##      ##STR1060##      ##STR1061##      ##STR1062##      ##STR1063##      ##STR1064##      ##STR1065##      ##STR1066##      ##STR1067##      ##STR1068##

Method T

This variation of Method Q can be used when the drug contains one ormore NH₂ and OH functions which are to be protected. The protectinggroups, for example, benzyloxycarbonyl for amino functions andpivalyloxy for hydroxyl functions, are introduced as described inMethods R and S, in the sequence considered most convenient. (Obviously,other protecting groups can be introduced instead.) The carboxylfunction(s) are then derivatized according to Method Q. Typically, thehydroxy protecting group(s) are introduced first and are retainedthroughout the process, while the amino protecting group(s) aregenerally removed earlier, frequently prior to formation of thequaternary derivative of formula (II).

The representative drugs depicted below may be derivatized in thismanner to the corresponding compounds of formulas (II) and (I).

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR1069##      ##STR1070##      ##STR1071##      ##STR1072##      ##STR1073##      ##STR1074##      ##STR1075##      ##STR1076##      ##STR1077##

Method U

The drug is first reacted with ethylene glycol (or otherdihydroxyalkanol having up to 8 carbon atoms), in the presence of asuitable coupling agent such as dicyclohexylcarbodiimide, to convert the--COOH function(s) to the corresponding

    --COOCH.sub.2 CH.sub.2 OH

(or ##STR1078## group(s). Then, a N-protected amino acid, such asN-benzyloxycarbonylglycine, which has been prepared as described inMethod A, is reacted therewith in the presence ofdicyclohexylcarbodiimide or other appropriate coupling agent. Removal ofthe protecting group, e.g. by catalytic hydrogenation, affords aderivative of the drug in which the original --COOH group(s) has/have,in the case of utilizing ethylene glycol and glycine, been converted tothe structure ##STR1079## That intermediate is then reacted with acompound of the formula ##STR1080## or the like, prepared as describedin Method J, in the presence of a coupling agent such asdicyclohexylcarbodiimide, to give the desired quaternary derivative offormula (II). Subsequent reduction to the corresponding dihydroderivative of formula (I) proceeds as described in Method A.

The drugs depicted below may be derivatized in this manner to thecorresponding compounds of formulas (II) and (I), as may the remainingdrugs mentioned with Method Q.

The procedure described above may be repeated utilizing a reactant ofthe formula ##STR1081## or the like, prepared as described in Method J,in place of the intermediate of the formula ##STR1082##

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR1083##      ##STR1084##      ##STR1085##      ##STR1086##      ##STR1087##      ##STR1088##      ##STR1089##      ##STR1090##      ##STR1091##      ##STR1092##      ##STR1093##      ##STR1094##      ##STR1095##      ##STR1096##      ##STR1097##      ##STR1098##      ##STR1099##      ##STR1100##      ##STR1101##      ##STR1102##

Method V

A drug containing one --COOH function is reacted with an equivalentamount of inositol, in the presence of dicyclohexylcarbodiimide or othersuitable coupling agent, to convert the --COOH function to a group ofthe structure ##STR1103## Reaction of that intermediate with nicotinuricacid, in the presence of a suitable coupling agent, or with an activatedester of nicotinuric acid, affords an intermediate in which the original--COOH has been converted to ##STR1104## wherein each R is H or##STR1105## the number of original hydroxy groups esterified varyingwith the amount of nicotinuric acid employed. Subsequent quaternizationand reduction are carried out as in Method A.

The drugs depicted below may be derivatized in this manner to thecorresponding compounds of formulas (II) and (I), as may the remainingdrugs mentioned with Method Q which contain a single --COOH function.

Alternatively, the above procedure may be repeated, replacingnicotinuric acid with an analogous starting material, prepared byreacting the selected amino acid with the acid chloride of nicotinicacid, of picolinic acid, or isonicotinic acid, of 3-quinolinecarboxylicacid, of 4-isoquinolinecarboxylic acid or the like.

Repetition of the procedure of the first paragraph of this methodutilizing a greater amount of the drug (e.g. 2 to 5 or more moles permole of inositol) provides an intermediate containing from 2 to 5 acidresidues and from 4 to 1 hydroxyl groups. That intermediate is thenreacted with nicotinuric acid to convert at least one hydroxyl group tothe corresponding ##STR1106## group. Subsequent formation of thequaternary and reduction proceed as in Method A.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR1107##      ##STR1108##      ##STR1109##      ##STR1110##      ##STR1111##      ##STR1112##      ##STR1113##      ##STR1114##      ##STR1115##      ##STR1116##      ##STR1117##      ##STR1118##      ##STR1119##      ##STR1120##      ##STR1121##      ##STR1122##      ##STR1123##      ##STR1124##      ##STR1125##      ##STR1126##      ##STR1127##      ##STR1128##      ##STR1129##      ##STR1130##      ##STR1131##      ##STR1132##      ##STR1133##      ##STR1134##      ##STR1135##      ##STR1136##

Method W

The drug is first reacted with 1,2-propylene glycol (or otherdihydroxyalkanol having up to 8 carbon atoms), in the presence of asuitable coupling agent such as dicyclohexylcarbodiimide, to convert the--COOH function(s) to the corresponding ##STR1137## (or other##STR1138## group(s). The resultant intermediate is then reacted withnicotinuric acid, in the presence of an appropriate coupling agent, orwith an activated ester of nicotinuric acid,to give an intermediate ofthe partial formula ##STR1139## Subsequent quaternization and reductionare carried out as in Method A.

The drugs depicted below may be derivatized in this manner to thecorresponding compounds of formulas (II) and (I), as may the remainingdrugs mentioned with Method Q.

Alternatively, the above procedure may be repeated, replacingnicotinuric acid with an analogous starting material, prepared byreacting the selected amino acid with the acid chloride of nicotinicacid, of picolinic acid, of isonicotinic acid, of 3-quinolinecarboxylicacid, of 4-isoquinolinecarboxlic acid or the like.

      STARTING MATERIAL QUATERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR1140##      ##STR1141##      ##STR1142##      ##STR1143##      ##STR1144##      ##STR1145##      ##STR1146##      ##STR1147##      ##STR1148##      ##STR1149##      ##STR1150##      ##STR1151##      ##STR1152##      ##STR1153##      ##STR1154##      ##STR1155##      ##STR1156##      ##STR1157##

Method X

Glucosamine, of the structural formula ##STR1158## is reacted withnicotinuric acid, using equimolar amounts of the reactants, in thepresence of a suitable coupling agent such as dicyclohexylcarbodiimide,or with an activated ester of nicotinuric acid. The resultantintermediate of the formula ##STR1159## is then reacted with a drugcontaining one reactive --COOH function, in the presence ofdicyclohexylcarbodiimide or other appropriate coupling agent, replacingone or more of the hydroxy groups with acid residue(s), the number ofgroups replaced varying with the relative amounts of reactants used.

The drugs depicted below may be derivatized in this manner to thecorresponding compounds of formulas (II) and (I), as may the remainingdrugs mentioned with Method Q which contain a single --COOH group.

Alternatively, the above procedure may be repeated, replacingnicotinuric acid with an analogous starting material, prepared byreacting the selected amino acid with the acid chloride of nicotinicacid, of picolinic acid, of isonicotinic acid, of 3-quinolinecarboxylicacid, of 4-isoquinolinecarboxylic acid or the like.

      STARTING MATERIAL QUARTERNARY INTERMEDIATE (CATION)  DIHYDRO DERIVATIVE      ##STR1160##      ##STR1161##      ##STR1162##      ##STR1163##      valproic acid      ##STR1164##      ##STR1165##      ##STR1166##      ##STR1167##      nafcillin      ##STR1168##      ##STR1169##      ##STR1170##      ##STR1171##      chlorombucil      ##STR1172##      ##STR1173##      ##STR1174##      ##STR1175##      naproxen      ##STR1176##      ##STR1177##      ##STR1178##      ##STR1179##      DACH      ##STR1180##      ##STR1181##      ##STR1182##      ##STR1183##      Iodomide

Method Y

The procedure of Method W is repeated, using ethylene glycol in place of1,2-propylene glycol.

The drugs depicted below may be derivatized in this manner to thecorresponding compounds of formulas (II) and (I), as may the remainingdrugs mentioned with Method Q.

Alternatively, nicotinuric acid may be replaced in this process with ananalogous starting material, as described in the last paragraph ofMethod W.

      STARTING MATERIAL QUARTERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR1184##      ##STR1185##      cephalothin      ##STR1186##      ##STR1187##      ##STR1188##      ##STR1189##      valproic acid      ##STR1190##      ##STR1191##      cefoxitin      ##STR1192##      ##STR1193##      ##STR1194##      ##STR1195##      oxolinic acid      ##STR1196##      ##STR1197##      chlorombucil      ##STR1198##      ##STR1199##      ##STR1200##      DACH      ##STR1201##      ##STR1202##      ##STR1203##      methotrexate      ##STR1204##      ##STR1205##      ##STR1206##      ##STR1207##      ##STR1208##      ##STR1209##      ##STR1210##      ibuprofen      ##STR1211##      ##STR1212##      ##STR1213##      benzylpenicillin      ##STR1214##      ##STR1215##      ##STR1216##      naproxen      ##STR1217##      ##STR1218##      ##STR1219##      cephapirin      ##STR1220##      ##STR1221##      ##STR1222##       hetacillin      ##STR1223##      ##STR1224##      ##STR1225##      ##STR1226##      o-iodohippuric acid      ##STR1227##      ##STR1228##      ##STR1229##      iothalamic acid

Method Z

The process of the first paragraph of Method Q is repeated, using anaminoalkanol of the formula ##STR1230## in place of 2-aminoethanol.

The drugs depicted below may be derivatized in this manner to thecorresponding compounds of formulas (II) and (I), as may the remainingdrugs mentioned with Method Q.

The process variation described in the second paragraph of Method Q mayalso be applied to Method Z.

      STARTING MATERIAL QUARTERNARY INTERMEDIATE (CATION) DIHYDRO DERIVATIVE      ##STR1231##      ##STR1232##      chlorambucil      ##STR1233##      ##STR1234##      ##STR1235##      ##STR1236##      ##STR1237##      ##STR1238##      cefoxitin      ##STR1239##      ##STR1240##      ##STR1241##      ##STR1242##      ibuprofen      ##STR1243##      ##STR1244##      ##STR1245##      naproxen      ##STR1246##      ##STR1247##      ##STR1248##      iothalamic acid

IV. Methods for Salt Formation

An ether solution of a compound of formula (I) is treated with anequivalent amount of anhydrous p-toluenesulfonic acid dissolved in dryether. Mixing at room temperature is continued until the imminium saltprecipitates out of solution. The salt is then removed by filtration.

Imminium salts which may be prepared in this manner include thosederived from the following representative compounds of formula (I):##STR1249##

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

In the examples immedately to follow, NMR spectra were determined bymeans of a Varian EM360A spectrometer. All chemical shifts reported arein δ units (parts per million) relative to tetramethylsilane.

EXAMPLE l

Nicotinuric acid (413 mg, 2.29 mmol), having the structural formula##STR1250## was combined with dicyclohexylcarbodiimide (519 mg, 10%excess) in dry pyridine (70 ml) and to that mixture was added a solutionof L-DOPA 0-methyl ester hydrochloride (567 mg, 2.29 mmol), having thestructural formula ##STR1251## in dry pyridine (10 ml) at roomtemperature. The resultant reaction mixture was stirred at roomtemperature for 24 hours, then was cooled to 0° C. The dicyclohexylureawhich precipitated was removed by filtration and washed withacetonitrile. The filtrate was evaporated to dryness in vacuo to leave ayellow oil, which was taken up in a minimum of acetonitrile. Undissolveddicyclohexylurea was removed by filtration. In this manner, 97% of thetheoretical yield of dicyclohexylurea was removed. The product was driedby means of an oil pump for several hours to afford a pale orangehygroscopic foam. There was thus obtained, in nearly quantitative yield,N-(N'-nicotinoyl)glycyl L-DOPA 0-methyl ester, having the structuralformula ##STR1252## NMR(dmso d₆) 9.2(bs, 1H, pyridine H-2); 8.8(m, 1H,pyridine H-6); 8.4(m, 1H, pyridine H-4); 8.1(m, 1H, pyridine H-5);7.5-7.8(m); 6.4-6.8(m, 3H, Ar); 5.2-6.8(broad, NH, exchangeable); 4.5(m,1H, ArCH₂ CH); 3.9(d, 2H, CONHCH₂); 3.7(s, 3H, OCH₃); 2.7-2.9(m, ARCH₂).The product may also be named3-(3,4-dihydroxy)phenyl-2-[N-(nicotinoyl)glycyl]aminopropanoic acidmethyl ester.

EXAMPLE 2

The product of Example 1 (373 mg, 1 mmol) was suspended in chloroform(15 ml) and triethylamine (0.30 ml, 2.1 mmol) was added. Pivaloylchloride (264 ml, 2.2 mmol) was added and the mixture was stirred atreflux overnight. Volatile substances were removed in vacuo, leaving apale orange solid. The solid residue was taken up in chloroform (30 ml)and washed, first with aqueous sodium bicarbonate solution (15 ml, 0.5%NaHCO₃) and then with water (10 ml). The aqueous phase was twicere-extracted with chloroform, using 20 ml portions of solvent, and thecombined organic layers were dried over anhydrous sodium sulfate.Evaporation to dryness left a dark orange oil which foamed on prolongedvacuum treatment. There were thus obtained 380 mg of3-(3,4-dipivaloyloxy)phenyl-2-[N-(nicotinoyl)glycyl]aminopropanoic acidmethyl ester, having the structural formula ##STR1253## NMR(CDCl₃)9.1(bs, 1H, pyridine H-2); 8.8(d, 1H, pyridine H-6); 8.0-8.3(dt, 1H,pyridine 4-H); 7.8(t, 2H, NH-exchangeable); 7.3(m, pyridine H-5);6.95(bs, 3H, OCH₃); 3.2(m, 2H, ArCH₂); 1.3(s, ˜18H);+impurity, extrat-butyl peaks.

EXAMPLE 3

The product of Example 2 (300 mg,˜0.55 mmol) in dry acetonitrile (10 ml)was treated with methyl iodide (180 ml,˜5-fold excess) at roomtemperature for 10 minutes. The mixture was then brought to the refluxtemperature and maintained at that temperature for one hour, thenallowed to stand at room temperature for two days. Evaporation todryness gave an orange, hydroscopic solid/foam. The resultant quaternarysalt has the formula ##STR1254## NMR(CD₃ CN) 9.6(bs, 1H, pyridiniumH-2); 8.7-9.1(m, 2H, pyridinium H-4, H-6); 8.2-8.6(m, ˜1H,NH-exchangeable), 7.1-7.3(bs, 3H, Ar); 4.6-4.9(m, 1H, ArCH₂ CH); 4.5(s,3H, ⁺ NCH₃); 4.1(d, 2H, NCH₂ CO.NH); 3.1-3.3(d, distorted, 2H, ArCH₂);1.35(s, 18H) ⁺ impurity, t-butyl.

EXAMPLE 4

The product of Example 3 (250 mg, 0.365 mmol) in cold deareated (N₂)water (50 ml) was treated with sodium bicarbonate (123 mg, 4equivalents) and sodium dithionite (196 mg, 3 equivalents). Ether (50ml) was added and the reaction mixture was stirred under nitrogen at 0°C. for 45 minutes. A portion of the ether layer was removed after 2minutes and the ultraviolent absorption spectra was examined. Absorptiondue to the dihydropyridine moiety was visible at 356 nm. Furtheraliquots were removed every 10 minutes and similarly examined. Whenthere was no longer any change in the ratio of quaternary to dihydroabsorption, the reaction mixture was separated into aqueous and organiclayers. The aqueous layer was extracted three times with 20 ml portionsof ethyl ether and the combined organic layers were washed with coldwater (20 ml), dried over anhydrous sodium sulfate and evaporated todryness. The residual yellow-orange oil was taken up in chloroform (15ml) and filtered through a plug of neutral alumina. Evaporation todryness gave a yellow-orange oil/foam which was slowly oxidized bymethanolic silver nitrate solution. The product has the formula##STR1255## NMR(CDCl₃) 6.8-7.1(m, 4H, Ar and pyridine H-2); 5.9-6.2(m,pyridine H-6); 5.6(d, 1H, pyridine H-5); 4.5-4.9(m, 2H, ArCH₂ CH andNH); 3.95(t, 2H, glycine CH₂); 3.7(s, 3H, OCH₃); 3.0-3.3(m, 4H, ArCH₂and pyridine C-4 H₂); 2.9(s, 3H, NCH₃); 1.3(s, 18H)+^(t) Bu impurity.

The present invention can thus be seen to provide two major classes ofnovel chemical compounds, i.e. the compounds of general formula (I)above, including their salts, and the compounds of general formula (II)above, wherein D is the residue of a centrally acting drug containing atleast one reactive functional group selected from the group consistingof amino, hydroxyl, mercapto, carboxyl, amide and imide and the otherstructural variables are as defined broadly above. Within each of thesemajor classes, the following subclasses are particularly noteworthy:

(A) Compounds of formulas (I) and (II) wherein the D portion of thecompound of formula (I) or (II) is identical to the correspondingportion of the centrally acting drug from which D can be considered tobe derived, and the carrier is attached through an amino functionalgroup in the drug. Preferred groups of compounds in this subclassinclude the following:

(1) Cerebral stimulants, including sympathomimetic amine-type cerebralstimulants, such as amphetamine, dextroamphetaine, levamphetamine,aletamine, cypenamine, tyramine, phentermine, methamphetamine,fencamfamin, zylofuramine, phenethylamine, etryptamine andtranylcypromine; tricyclic antidepressant-type cerebral stimulants,expecially dibenzazepines and their analogues, e.g. desipramine,nortriptyline, protriptyline, maprotiline, octriptyline, and many othercerebral stimulants, alerting agents and antidepressants of varioustypes, as exemplified by amiphenazole, amedalin, cartazolate, daledalin,fluoxetine, nisoxetine, bupropion, difluamine and methylphenidate.

(2) Neurotransmitters, such as dopamine, histamine, tryptamine andserotonin.

(3) Narcotic analgesics, such as anileridine, noracymethadol andpiminodine.

(4) Hypotensives, such as clonidine, hydralazine, bethanidine,guanethidine, debrisoquin, propranolol and prizidilol.

(5) Sympathomimetic amines, such as ephedrine, oxymetazoline andpseudoephedrine.

(6) Anticancer and antitumor agents, such as doxorubicin and daunomycin.

(7) Antiviral agents, such as amantadine,2-guanidino-4,5-di-n-propyloxazole, 2-guanidino-4,5-diphenyloxazole,glucosamine and 6-amino-6-deoxy-D-glucose

(8) Antibiotic and antibacterial agents, such as phenazopyridine,bacampicillin and pivampicillin.

(9) Sedatives, muscle relaxants, anticonvulsants, tranquilizers(including benzodiazepine tranquilizers) e.g. benzoctamine, tracazolate,chlordiazepoxide, tiletamine and aminoglutethimide.

(10) Diagnostics, including radiolabeled diagnostics, e.g.iodometaraminol.

(B) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains an amino function through which thecarrier is attached and also contains at least one --OH functionalgroup, and D in formula (I) or (II) contains, in place of the hydrogenatom of at least one of the --OH groups in the drug, at least onehydrolytically or metabolically cleavable hydroxyl protective group.Within subclass (B), preferred compounds are those in which D is aprotected residue of a neurotransmitter, such as dopamine or serotonin;a cerebral stimulant, such as tyramine; a sympathomimetic amine, such asephedrine, phenylephrine or pseudoephedrine; a CNS prostaglandin, suchas PGD₂ ; an adrenergic agent, such as norepinephrine or epinephrine; ananticancer or antitumor agent, such as pentostatin; an antiviral such asglucosamine or 6-amino-6-deoxy-D-glucose; or a hypotensive, such asatenolol or metoprolol.

(C) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains an amino function through which thecarrier is attached and also contains at least one --COOH functionalgroup, and D in formula (I) or (II) contains, in place of the hydrogenatom of at least one of the --COOH groups, at least one hydrolyticallyor metabolically cleavable carboxyl protective group. Preferredcompounds within this subclass are those in which D is a protectedresidue of anticancer and antitumor agents, e.g. melphalan, DON,L-alanosine and acivicin; antibiotics, especially penicillins such asamoxacillin and ampicillin and cephalosporins such as cephalexin,cefroxadine and ceforanide; hypotensives such as methyldopa andfurosemide; and dopaminergic agents such as L-DOPA.

(D) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains an amino function through which thecarrier is attached and also contains at least one --OH functional groupand at least one --COOH functional group, and D in formula (I) or (II)contains, in place of the hydrogen atom of at least one of the --OHfunctional groups and at least one of the --COOH functional groups insaid drug, respectively, at least one hydrolytically or metabolicallycleavable hydroxyl protective group and at least one hydrolytically ormetabolically cleavable carboxyl protective group. Of particularinterest are the compounds in which D is a protected residue of ahypotensive, e.g. methyldopa; or a sympathetic stimulant/dopaminergicagent e.g. levodopa.

(E) Compounds of formulas (I) and (II) wherein the D portion of thecompound of formula (I) or (II) is identical to the correspondingportion of the drug from which D can be considered to be derived and thecarrier is attached through a hydroxyl or mercapto functional group inthe drug. Preferred groups of compounds in this subclass include thefollowing:

(1) Tranquilizers, including benzodiazepines, such as oxazepam, temazeamand lorazepam; phenothiazines, such as carphenazine, fluphenazine,acetophenazine and the like; and other tranquilizers such ashalopertdol, clopenthixol and hydroxyzine.

(2) Steroids, including androgens, e.g. testosterone; progestins, e.g.norgestrel and norethynodrel; estrogens, e.g. natural estrogens such asestradiol and semi-synthetic estrogens such as mestranol; andantiinflammatory steroids such as cortisone, hydrocortisone,triamcinolone and the like.

(3) Narcotic analgesics, such as codeine, pentazocine and morphine.

(4) Narcotic antagonists and mixed agonists/antagonists, e.g.nalorphine, naloxone, buprenorphine, nalbuphine and butorphanol.

(5) Cerebral stimulants, including tricyclic anti depressants such asopipramol and centrally active hydroxylated metabolites of tricyclicantidepressants, e.g. 2-hydroxyimipramine.

(6) Anticancer and antitumor agents, e.g. mitoxantrone, etoposide,hydroxyurea and Ara-AC.

(7) Antivitals, e.g. ribavarin and acyclovir.

(8) Non-steroidal antiinflammatory agents, e.g. clonixeril and naproxol.

(9) Hypotensives, e.g. prizidilol and nadolol.

(10) Diagnostics, e.g. iopydol.

(F) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains a hydroxyl or mercapto functionthrough which the carrier is attached and also contains at least oneamino functional group, and D in formula (I) or (II) contains, in placeof a hydrogen atom of at least one of the amino groups in the drug, atleast one amino protective group. Of particular interest are derivativesof neurotransmitters, stimulants, sympathetic amines, anticancer orantitumor agents, adrenergic agents and antiviral agents. The stimulantsinclude centrally active metabolites of tricyclic antidepressants (e.g.2-hydroxydesipramine).

(G) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains a hydroxyl or mercapto functionthrough which the carrier is attached and also contains at least onecarboxyl group, and D in formula (I) or (II) contains, in place of thehydrogen atom of at least one of the carboxyl groups in the drug, atleast one hydrolytically or metabolically cleavable carboxyl protectivegroup. Of particular interest here are the derivatives of valproic acidmetabolite anticonvulsants and CNS prostaglandins.

(H) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains an amide or imide or low pKaprimary or secondary amine function through which the carrier isattached and the D portion of the compound of formula (I) or (II) isidentical to the corresponding portion of the drug from which D can beconsidered to be derived. Especially significant members of this groupare the hydantoin anticonvulsants, e.g. phenytoin, ethotoin andmephenytoin, as well as other anticonvulsants, e.g. phenobarbital,aminoglutethimide, progabide and valpromide; tranquilizers, e.g.benzodiazepine-type tranquilizers such as bromazepam and oxazepam, andcentrally active N-desmethyl metabolites of N-methylated benzodiazepinetranquilizers; hypnotics; nonsteroidal antiinflammatory agents;anticancer agents such as cyclophosphamide; antidepressants, such assulpiride; antibiotics, especially tetracyc-lines; and antivirals, suchas trifluridine.

(I) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains an amide or imide or low pKaprimary or secondary amine function through which the carrier isattached and the drug also contains at least one hydroxyl group, D informula (I) or (II) containing, in place of the hydrogen atom of atleast one hydroxyl group in the drug, at least one hydrolytically ormetabolically cleavable hydroxyl protective group. Significant membersof this group include antivitals such as trifluridine and benzodiazepinetranquilizers such as oxazepam.

(J) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains an amide or imide or low pKaprimary or secondary amine function through which the carrier isattached and the drug also contains at least one carboxyl functionalgroup, D in formula (I) or (II) containing, in place of the hydrogenatom of at least one --COOH in the drug, at least one hydrolytically ormetabolically cleavable carboxyl protective group. Especiallysignificant members of this group include anticancer and antitumoragents, antibiotics (particularly penicillins and cephalosporins) andCNS anticholinergics.

(K) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains a --COOH function through which thecarrier is attached, and the D portion of the compound of formula (I) or(II) is identical to the corresponding portion of the drug from which Dcan be considered to be derived. Especially significant members of thisgroup include nonsteroidal antiinflammatory agents such as naproxen,ibuprofen and the like; diagnostics, including radiolabeled ones such aso-iodohippuric acid and iothalamic acid, as well as the corresponding"cold" compounds; CNS prostaglandins, such as PGD₂ ; antibiotics,especially cephalosporins and penicillins; anticonvulsants,. e.g.valproic acid and SL 75102; anticancer and antitumor agents, e.g.chlorambucil, DACH, and methotrexate.

(L) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains a --COOH function through which thecarrier is attached and the drug also contains at least one hydroxylfunction, D in formula (I) or (II) containing, in place of the hydrogenatom of at least one --OH in the drug, at least one hydrolytically ormetabolically cleavable hydroxyl protective group. Within this class,derivatives of valproic acid metabolite-type anticonvulsants and NSAID'sare especially noteworthy.

(M) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains a --COOH function through which thecarrier is attached and the drug also contains at least one aminofunction, D in formula (I) or (II) containing, in place of a hydrogenatom of at least one of the amino functions in the drug, at least oneamino protective group. Significant members of this group includepenicillins antibiotics, cephalosporin antibiotics and anticancer andantitumor agents.

(N) Compounds of formulas (I) and (II) wherein the drug from which D canbe considered to be derived contains a --COOH function through which thecarrier is attached and the drug also contains at least one aminofunction and at least one hydroxyl function, D in formula (I) or (II)containing, in place of a hydrogen atom of at least one amino functionand in place of the hydrogen atom of at least one hydroxyl function,respectively, at least one amino protective group and at least onehydrolytically or metabollically cleavable hydroxyl protective group.Particularly significant members of this class include dopaminergicagents, hypotensive agents and antibiotics.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims.

What is claimed is:
 1. A compound of the formula ##STR1256## or anontoxic pharmaceutically acceptable salt thereof, wherein D is theresidue of a centrally acting drug having at least one reactive hydroxylfunctional group, said drug being a steroid sex hormone orantiinflammatory steroid, said residue being characterized by theabsence of a hydrogen atom from at least one reactive hydroxylfunctional group in said drug; n is a positive integer equal to thenumber of said functional groups from which a hydrogen atom is absent;and (DHC) is a radical of the formula ##STR1257## wherein the alkylenegroup can be straight or branched and can contain 1 to 3 carbon atoms;R₀ is hydrogen, methyl, ##STR1258## --CH₂ COOH or --CH₂ CH₂ COOH; p is 1or 2, provided that, when p is 2, then the alkylene groups can be thesame or different and the R₀ radicals can be the same or different; thedotted line in formula (a') indicates the presence of a double bond ineither the 4 or 5 position of the dihydropyridine ring; the dotted linein formula (d') indicates the presence of a double bond in either the 2or 3 position of the dihydroquinoline ring; R₁ is C₁ -C₇ alkyl, C₁ -C₇haloalkyl or C₇ -C₁₀ aralkyl; the carbonyl-containing grouping informula (a') can be attached at the 2, 3 or 4 position of thedihydropyridine ring; the carbonyl-containing grouping in formula (d')can be attached at the 2, 3 or 4 position of the dihydroquinoline ring;and the carbonyl-containing grouping in formula (g') can be attached atthe 1, 3 or 4 position of the dihydroisoquinoline ring.
 2. A compoundaccording to claim 1, wherein (DHC) comprises the reduced form of anN-substituted nicotinic acid derivative.
 3. A compound according toclaim 1, wherein (DHC) comprises the reduced form of a trigonelline. 4.A compound according to claim 1, wherein n is
 1. 5. A compound accordingto claim 1, wherein R_(o) is hydrogen.
 6. A compound according to claim1, wherein p is
 1. 7. A compound according to claim 1, wherein thesteroid is hydrocortisone, betamethasone, dexamethasone, cortisone,flumethasone, fluprednisolone, meprednisone, methylprednisolone,prednisolone, prednisone, triamcinolone, cortodoxone, fludrocortisone,flurandrenolide, paramethasone, testosterone, methyltestosterone,ethinyl estradiol, norgestrel, mestranol, norethindrone, ethisterone,estradiol, estriol, estrone, dimethisterone, allylestrenol, cingestol,ethynerone, lynestrenol, norethynodrel, norgesterone, norvinisterone,ethynodiol, oxogestone, tigestol or quinestrol.
 8. A compound accordingto claim 7, wherein the steroid is dexamethasone.
 9. A compoundaccording to claim 1, wherein the alkylene group has 1 carbon atom. 10.A compound according to claim 1, wherein R₀ is hydrogen, methyl,##STR1259##
 11. The compound according to claim 1, which has theformula: ##STR1260##
 12. A compound according to claim 1, wherein R₁ isCH₃.
 13. A compound according to claim 1, wherein (DHC) has formula (a')wherein the carbonyl-containing grouping is attached at the 3-positionof the dihydropyridine ting, or wherein (DHC) has formula (d') whereinthe carbonyl-containing grouping is attached at the 3-position of thedihydroquinoline ting, or wherein (DHC) has formula (g') wherein thecarbonyl-containing grouping is attached at the 4-position of thedihydroisoquinoline ring.
 14. A pharmaceutical composition, in unitdosage form, said composition comprising:(i) an amount of a compound asclaimed in claim 1, or a nontoxic pharmaceutically acceptable saltthereof, sufficient to release a pharmacologically effective amount of asteroid sex hormone or antiinflammatory steroid to the brain; and (ii) anontoxic pharmaceutically acceptable carrier therefor.
 15. Apharmaceutical composition as claimed in claim 14, said compositionbeing a pharmaceutically acceptable sustained release composition.
 16. Aquaternary salt of the formula ##STR1261## wherein D is the residue of acentrally acting drug having at least one reactive hydroxyl functionalgroup, said drug being a steroid sex hormone or antiinflammatorysteroid, said residue being characterized by the absence of a hydrogenatom from at least one reactive hydroxyl functional group in said drug;n is a positive integer equal to the number of said functional groupsfrom which a hydrogen atom is absent; and (QC⁺) is a radical of theformula ##STR1262## wherein the alkylene group can be straight orbranched and can contain 1 to 3 carbon atoms; R₀ is hydrogen, methyl,##STR1263## p is 1 or 2, provided that, when p is 2, then the alkylenegroups can be the same or different and the R₀ radicals can be the sameor different; R₁ is C₁ -C₇ alkyl, C₁ -C₇ haloalkyl or C₇ -C₁₀ aralkyl;the carbonyl-containing grouping in formula (a) can be attached at the2, 3 or 4 position of the pyridinium ring; the carbonyl-containinggrouping in formula (d) can be attached at the 2, 3 or 4 position of thequinolinium ring; and the carbonyl-containing grouping in formula (g)can be attached at the 1, 3 or 4 position of the isoquinolinium ring; Y⁻is the anion of a pharmaceutically acceptable organic or inorganic acid;t is the valence of the acid anion; and q is the number which whenmultiplied by t is equal to n.
 17. A quaternary salt according to claim16, wherein the steroid is hydrocortisone, betamethasone, dexamethasone,cortisone, flumethasone, fluprednisolone, meprednisone,methylprednisolone, prednisolone, prednisone, triamcinolone,cortodoxone, fludrocortisone, flurandrenolide, paramethasone,testosterone, methyltestosterone, ethinyl estradiol, norgestrel,mestranol, norethindrone, ethisterone, estradiol, estriol, estrone,dimethisterone, allylestrenol, cingestol, ethynerone, lynestrenol,norethynodrel, norgesterone, norvinisterone, ethynodiol, oxogestone,tigestol or quinestrol.
 18. A quaternary salt according to claim 17,wherein the steroid is dexamethasone.
 19. A quaternary salt according toclaim 16, wherein the alkylene group has 1 carbon atom.
 20. A quaternarysalt according to claim 16, wherein R₀ is hydrogen, methyl, ##STR1264##21. A quaternary salt according to claim 16, wherein (QC⁺) comprises theoxidized form of an N-substituted nicotinic acid derivative.
 22. Aquaternary salt according to claim 16, wherein (QC⁺) comprises theoxidized form of a trigonelline.
 23. A quaternary salt according toclaim 16, wherein n is
 1. 24. A quaternary salt according to claim 16,wherein R₀ is hydrogen.
 25. A quaternary salt according to claim 16,wherein p is
 1. 26. A quaternary salt according to claim 16, wherein R₁is CH₃.
 27. A quaternary salt according to claim 16, wherein (QC⁺) hasformula (a) wherein the carbonyl-containing grouping is attached at the3-position of the pyridinium ring, or wherein (QC⁺) has formula (d)wherein the carbonyl-containing grouping is attached at the 3-positionof the quinolinium ring, or wherein (QC⁺) has formula (g) wherein thecarbonyl-containing grouping is attached at the 4-position of theisoquinolinium ring.
 28. The quaternary salt according to claim 16, thecation of which has the formula: ##STR1265##